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How does an inhibitory synapse communicate to the cell body of a neuron?

How does an inhibitory synapse communicate to the cell body of a neuron?



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I picture a neuron as having multiple trees of dendrites attached to the cell body with a single axon leaving the cell body. I believe the cell body near the axon root makes the decision to fire or not fire an action potential.

  • If the neuron has both excitatory and inhibitory synapses in the dendrite trees, how do these communicate to the cell body?

  • Does something like an action potential get transmitted down the dendritic trees to the cell body?

  • What is the difference between the excitatory and inhibitory signals that are transmitted?


From your comment to nico's good answer, it seems that your question is really about how synaptic potentials propagate through dendrites.

Canonically, synaptic potentials travel passively along membranes and is described by cable theory. The cable equation describes how the voltage will change over time and space along a cable. The theory was originally developed for signal decay in trans-Atlantic telegraph cables, but the principle holds for a voltage-independent length of membrane like a dendrite.

A key point is that the potential change "seen" by the cell body is different from the potential change seen locally at the site of the synapse itself. In fact, the voltage decays exponentially with increasing distance from the synapse. The extent of the signal decay is governed by the axial resistance (influenced by dendritic diameter), the membrane resistance, and membrane capacitance, and the branching pattern. A common neuron modeling environment called NEURON is basically a fancy solver for the cable equation.

You'll note that a consequence of this signal decay is that synaptic location matters a lot. Given an identical synaptic potential, a very distal synapse will have much less of an effect on the soma than a more proximal dendrite. Sometimes, the synaptic strengths are scaled to compensate for this location issue (a distal synapse will have a much larger local potential change). Many inhibitory synapses capitalize on this location dependence and are located close to the soma to act as shunts for all signals coming from the dendritic tree. When activated, an inhibitory synapse will decrease the local membrane resistance thereby decreasing cell excitability.

Finally, I'll note that although we often talk about dendrites as being passive conductors, dendrites are actually quite active and have many voltage-dependent channels. The voltage-dependent phenomena in the dendrite complicates the use of pure cable theory to understand the dynamics of synaptic potentials. However, cable theory is still the essential foundation upon which our growing understanding of the active dendrite is built.


An inhibitory synapse works just like an excitatory one!

When a presynaptic neuron fires it will release a neurotransmitter at its terminal(s). This neurotransmitter can be excitatory or inhibitory, the main excitatory one in the central nervous system being glutamate and the main inhibitory one GABA.*

GABA and Glu are far from being the only neurotransmitters in the brain, they're just a classic example, so we'll stick with them. When the neurotransmitter is released it binds to receptors on the postsynaptic neuron (provided, of course, that the postsynaptic neuron expresses these receptors).

Various GABA and Glu receptors exist, both ionotropic (i.e. channel-receptors that let ions flow through the membrane upon binding of the ligand) and metabotropic (i.e. receptors which activate an intracellular pathway that does not per se start the flow of ions, but that can induce it or prevent it indirectly). For simplicity we'll stick to ionotropic receptors.

Glu binds to three types of ionotropic receptors: AMPA, NMDA and kainate receptors. These have different kinetics/properties, but the bottom line is that they let cations (positively charged ions, such as Na+ and Ca++) into the cell. When this happens a postsynaptic depolarization happens, which is named EPSP (excitatory post-synaptic potential).
So, if the resting membrane potential was, say, -57mV, it will become, for instance -52mV. This means that, if the threshold potential for firing an action potential were -43mV the cell, which first needed a 14mV depolarization to fire now will need a 9mV depolarization. If subsequent EPSP sum they can depolarize the cell sufficiently to reach threshold and let the cell fire.

This image from Wikipedia is quite self-explicatory: in this case 3 synaptic events generated 3 EPSPs that summed, making the cell depolarize enough to reach threshold potential, and generate an action potential, that will then propagate to the cell body.

GABA, on the other hand, binds to the GABA-A receptor, which is a chloride channel. In most cases, upon binding of GABA, GABA-A lets Cl- in the cell, effectively hypopolarizing it and generating an IPSP (inhibitory post-synaptic potential). The situation is the same (but opposite) to Glu, this time, though, the potential becomes more negative.

EPSP and IPSP can and do happen at the same time: as they can vary in frequency and intensity depending on the firing frequency and firing pattern of the presynaptic neuron, a pretty much continuous range of voltages can be achieved in the postsynaptic neuron.

Other controls over this process come from metabotropic receptors that can, for instance [de]phosphorylate (add or remove a phosphate group) ion channels modulating their permeability to ions or from the different kinetics of the different channels (for instance certain channels stay open for longer or open in a delayed manner etc), allowing for fine-tuning of the system.


*I am making a gross generalization here. A neurotransmitter is not excitatory or inhibitory per se, it depends on the context. For instance excitatory GABA synapses do exist.


Calsyntenin-3, an atypical cadherin, suppresses inhibitory basket- and stellate-cell synapses but boosts excitatory parallel-fiber synapses in cerebellum

Cadherins contribute to the organization of nearly all tissues, but the functions of several evolutionarily conserved cadherins, including those of calsyntenins, remain enigmatic. Puzzlingly, two distinct, non-overlapping functions for calsyntenins were proposed: As postsynaptic neurexin ligands in synapse formation, or as presynaptic adaptors for kinesin-mediated vesicular transport. Here, we show that acute CRISPR-mediated deletion of calsyntenin-3 in cerebellar Purkinje cells in vivo causes a large decrease in inhibitory synapses, but a surprisingly robust increase in excitatory parallel-fiber synapses. No changes in the dendritic architecture of Purkinje cells or in climbing-fiber synapses were detected. Thus, by promoting formation of an excitatory type of synapses and decreasing formation of an inhibitory type of synapses in the same neuron, calsyntenin-3 functions as a postsynaptic adhesion molecule that regulates the excitatory/inhibitory balance in Purkinje cells. No similarly opposing function of a synaptic adhesion molecule was previously observed, suggesting a new paradigm of synaptic regulation.


Nerve Impulse Transmission within a Neuron

For the nervous system to function, neurons must be able to send and receive signals. These signals are possible because each neuron has a charged cellular membrane (a voltage difference between the inside and the outside), and the charge of this membrane can change in response to neurotransmitter molecules released from other neurons and environmental stimuli. To understand how neurons communicate, one must first understand the basis of the baseline or ‘resting’ membrane charge.


Synaptic Transmission

The synapse or “gap” is the place where information is transmitted from one neuron to another. Synapses usually form between axon terminals and dendritic spines, but this is not universally true. There are also axon-to-axon, dendrite-to-dendrite, and axon-to-cell body synapses. The neuron transmitting the signal is called the presynaptic neuron, and the neuron receiving the signal is called the postsynaptic neuron. Note that these designations are relative to a particular synapse—most neurons are both presynaptic and postsynaptic. There are two types of synapses: chemical and electrical.

Chemical Synapse

Figure 6. This pseudocolored image taken with a scanning electron microscope shows an axon terminal that was broken open to reveal synaptic vesicles (blue and orange) inside the neuron. (credit: modification of work by Tina Carvalho, NIH-NIGMS scale-bar data from Matt Russell)

When an action potential reaches the axon terminal it depolarizes the membrane and opens voltage-gated Na + channels. Na + ions enter the cell, further depolarizing the presynaptic membrane. This depolarization causes voltage-gated Ca 2+ channels to open. Calcium ions entering the cell initiate a signaling cascade that causes small membrane-bound vesicles, called synaptic vesicles, containing neurotransmitter molecules to fuse with the presynaptic membrane. Synaptic vesicles are shown in Figure 6, which is an image from a scanning electron microscope.

Fusion of a vesicle with the presynaptic membrane causes neurotransmitter to be released into the synaptic cleft, the extracellular space between the presynaptic and postsynaptic membranes, as illustrated in Figure 7. The neurotransmitter diffuses across the synaptic cleft and binds to receptor proteins on the postsynaptic membrane.

Figure 7. Communication at chemical synapses requires release of neurotransmitters. When the presynaptic membrane is depolarized, voltage-gated Ca2+ channels open and allow Ca2+ to enter the cell. The calcium entry causes synaptic vesicles to fuse with the membrane and release neurotransmitter molecules into the synaptic cleft. The neurotransmitter diffuses across the synaptic cleft and binds to ligand-gated ion channels in the postsynaptic membrane, resulting in a localized depolarization or hyperpolarization of the postsynaptic neuron.

The binding of a specific neurotransmitter causes particular ion channels, in this case ligand-gated channels, on the postsynaptic membrane to open. Neurotransmitters can either have excitatory or inhibitory effects on the postsynaptic membrane, as detailed in Table 2. For example, when acetylcholine is released at the synapse between a nerve and muscle (called the neuromuscular junction) by a presynaptic neuron, it causes postsynaptic Na + channels to open. Na + enters the postsynaptic cell and causes the postsynaptic membrane to depolarize. This depolarization is called an excitatory postsynaptic potential (EPSP) and makes the postsynaptic neuron more likely to fire an action potential. Release of neurotransmitter at inhibitory synapses causes inhibitory postsynaptic potentials (IPSPs), a hyperpolarization of the presynaptic membrane. For example, when the neurotransmitter GABA (gamma-aminobutyric acid) is released from a presynaptic neuron, it binds to and opens Cl – channels. Cl – ions enter the cell and hyperpolarizes the membrane, making the neuron less likely to fire an action potential.

Once neurotransmission has occurred, the neurotransmitter must be removed from the synaptic cleft so the postsynaptic membrane can “reset” and be ready to receive another signal. This can be accomplished in three ways: the neurotransmitter can diffuse away from the synaptic cleft, it can be degraded by enzymes in the synaptic cleft, or it can be recycled (sometimes called reuptake) by the presynaptic neuron. Several drugs act at this step of neurotransmission. For example, some drugs that are given to Alzheimer’s patients work by inhibiting acetylcholinesterase, the enzyme that degrades acetylcholine. This inhibition of the enzyme essentially increases neurotransmission at synapses that release acetylcholine. Once released, the acetylcholine stays in the cleft and can continually bind and unbind to postsynaptic receptors.

Table 2. Neurotransmitter Function and Location
Neurotransmitter Example Location
Acetylcholine CNS and/or PNS
Biogenic amine Dopamine, serotonin, norepinephrine CNS and/or PNS
Amino acid Glycine, glutamate, aspartate, gamma aminobutyric acid CNS
Neuropeptide Substance P, endorphins CNS and/or PNS

Electrical Synapse

While electrical synapses are fewer in number than chemical synapses, they are found in all nervous systems and play important and unique roles. The mode of neurotransmission in electrical synapses is quite different from that in chemical synapses. In an electrical synapse, the presynaptic and postsynaptic membranes are very close together and are actually physically connected by channel proteins forming gap junctions. Gap junctions allow current to pass directly from one cell to the next. In addition to the ions that carry this current, other molecules, such as ATP, can diffuse through the large gap junction pores.

There are key differences between chemical and electrical synapses. Because chemical synapses depend on the release of neurotransmitter molecules from synaptic vesicles to pass on their signal, there is an approximately one millisecond delay between when the axon potential reaches the presynaptic terminal and when the neurotransmitter leads to opening of postsynaptic ion channels. Additionally, this signaling is unidirectional. Signaling in electrical synapses, in contrast, is virtually instantaneous (which is important for synapses involved in key reflexes), and some electrical synapses are bidirectional. Electrical synapses are also more reliable as they are less likely to be blocked, and they are important for synchronizing the electrical activity of a group of neurons. For example, electrical synapses in the thalamus are thought to regulate slow-wave sleep, and disruption of these synapses can cause seizures.


How are impulses transmitted across a synapse?

Read full answer here. Just so, how is a nerve impulse transmitted across a synapse?

A nervous impulse is transmitted across the synapse from a pre-synaptic neurone to a post-synaptic neurone through the use of neurotransmitter diffusion. This changes the voltage in the neurone causing the voltage-gated calcium channels on the pre-synaptic neurone to open.

Furthermore, how does a message of an impulse transmitted through a synapse? When neurons communicate, an electrical impulse triggers the release of neurotransmitters from the axon into the synapse. The neurotransmitters cross the synapse and bind to special molecules on the other side, called receptors. Receptors are located on the dendrites. Receptors receive and process the message.

Also to know is, how are impulses transmitted?

A nerve impulse is an electrical phenomenon that occurs because of a difference in electrical charge across the plasma membrane of a neuron. The action potential travels rapidly down the neuron's axon as an electric current. A nerve impulse is transmitted to another cell at either an electrical or a chemical synapse.

What causes the transmission of a nerve impulse?

The transmission of a nerve impulse along a neuron from one end to the other occurs as a result of electrical changes across the membrane of the neuron. The membrane of an unstimulated neuron is polarized&mdashthat is, there is a difference in electrical charge between the outside and inside of the membrane.


Contents

Neurotransmitters are stored in synaptic vesicles, clustered close to the cell membrane at the axon terminal of the presynaptic neuron. Neurotransmitters are released into and diffuse across the synaptic cleft, where they bind to specific receptors on the membrane of the postsynaptic neuron. [5] Binding of neurotransmitters may influence the postsynaptic neuron in either an excitation or inhibitory way, depolarizing or repolarizing it respectively.

Most of the neurotransmitters are about the size of a single amino acid however, some neurotransmitters may be the size of larger proteins or peptides. A released neurotransmitter is typically available in the synaptic cleft for a short time before it is metabolized by enzymes, pulled back into the presynaptic neuron through reuptake, or bound to a postsynaptic receptor. Nevertheless, short-term exposure of the receptor to a neurotransmitter is typically sufficient for causing a postsynaptic response by way of synaptic transmission.

Generally, a neurotransmitter is released at the presynaptic terminal in response to a threshold action potential or graded electrical potential in the presynaptic neuron. However, low level 'baseline' release also occurs without electrical stimulation.

Until the early 20th century, scientists assumed that the majority of synaptic communication in the brain was electrical. However, through histological examinations by Ramón y Cajal, a 20 to 40 nm gap between neurons, known today as the synaptic cleft, was discovered. The presence of such a gap suggested communication via chemical messengers traversing the synaptic cleft, and in 1921 German pharmacologist Otto Loewi confirmed that neurons can communicate by releasing chemicals. Through a series of experiments involving the vagus nerves of frogs, Loewi was able to manually slow the heart rate of frogs by controlling the amount of saline solution present around the vagus nerve. Upon completion of this experiment, Loewi asserted that sympathetic regulation of cardiac function can be mediated through changes in chemical concentrations. Furthermore, Otto Loewi is credited with discovering acetylcholine (ACh) – the first known neurotransmitter. [6]

There are four main criteria for identifying neurotransmitters:

  1. The chemical must be synthesized in the neuron or otherwise be present in it.
  2. When the neuron is active, the chemical must be released and produce a response in some targets.
  3. The same response must be obtained when the chemical is experimentally placed on the target.
  4. A mechanism must exist for removing the chemical from its site of activation after its work is done.

However, given advances in pharmacology, genetics, and chemical neuroanatomy, the term "neurotransmitter" can be applied to chemicals that:

  • Carry messages between neurons via influence on the postsynaptic membrane.
  • Have little or no effect on membrane voltage, but have a common carrying function such as changing the structure of the synapse.
  • Communicate by sending reverse-direction messages that affect the release or reuptake of transmitters.

The anatomical localization of neurotransmitters is typically determined using immunocytochemical techniques, which identify the location of either the transmitter substances themselves or of the enzymes that are involved in their synthesis. Immunocytochemical techniques have also revealed that many transmitters, particularly the neuropeptides, are co-localized, that is, a neuron may release more than one transmitter from its synaptic terminal. [7] Various techniques and experiments such as staining, stimulating, and collecting can be used to identify neurotransmitters throughout the central nervous system. [8]

There are many different ways to classify neurotransmitters. Dividing them into amino acids, peptides, and monoamines is sufficient for some classification purposes. [9]

  • Amino acids:glutamate, [10]aspartate, D-serine, gamma-Aminobutyric acid (GABA), [nb 1]glycine
  • Gasotransmitters:nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H2S)
  • Monoamines:dopamine (DA), norepinephrine (noradrenaline NE, NA), epinephrine (adrenaline), histamine, serotonin (SER, 5-HT)
      : dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline)
  • In addition, over 50 neuroactive peptides have been found, and new ones are discovered regularly. [ citation needed ] Many of these are co-released along with a small-molecule transmitter. Nevertheless, in some cases, a peptide is the primary transmitter at a synapse. Beta-Endorphin is a relatively well-known example of a peptide neurotransmitter because it engages in highly specific interactions with opioid receptors in the central nervous system.

    Single ions (such as synaptically released zinc) are also considered neurotransmitters by some, [12] as well as some gaseous molecules such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S). [13] The gases are produced in the neural cytoplasm and are immediately diffused through the cell membrane into the extracellular fluid and into nearby cells to stimulate production of second messengers. Soluble gas neurotransmitters are difficult to study, as they act rapidly and are immediately broken down, existing for only a few seconds.

    The most prevalent transmitter is glutamate, which is excitatory at well over 90% of the synapses in the human brain. [10] The next most prevalent is gamma-Aminobutyric Acid, or GABA, which is inhibitory at more than 90% of the synapses that do not use glutamate. Although other transmitters are used in fewer synapses, they may be very important functionally: the great majority of psychoactive drugs exert their effects by altering the actions of some neurotransmitter systems, often acting through transmitters other than glutamate or GABA. Addictive drugs such as cocaine and amphetamines exert their effects primarily on the dopamine system. The addictive opiate drugs exert their effects primarily as functional analogs of opioid peptides, which, in turn, regulate dopamine levels.

    List of neurotransmitters, peptides, and gaseous signaling molecules Edit

    Neurons form elaborate networks through which nerve impulses – action potentials – travel. Each neuron has as many as 15,000 connections with neighboring neurons.

    Neurons do not touch each other (except in the case of an electrical synapse through a gap junction) instead, neurons interact at contact points called synapses: a junction within two nerve cells, consisting of a miniature gap within which impulses are carried by a neurotransmitter. A neuron transports its information by way of a nerve impulse called an action potential. When an action potential arrives at the synapse's presynaptic terminal button, it may stimulate the release of neurotransmitters. These neurotransmitters are released into the synaptic cleft to bind onto the receptors of the postsynaptic membrane and influence another cell, either in an inhibitory or excitatory way. The next neuron may be connected to many more neurons, and if the total of excitatory influences minus inhibitory influences is great enough, it will also "fire". That is to say, it will create a new action potential at its axon hillock, releasing neurotransmitters and passing on the information to yet another neighboring neuron.

    Excitatory and inhibitory Edit

    A neurotransmitter can influence the function of a neuron through a remarkable number of mechanisms. In its direct actions in influencing a neuron's electrical excitability, however, a neurotransmitter acts in only one of two ways: excitatory or inhibitory. A neurotransmitter influences trans-membrane ion flow either to increase (excitatory) or to decrease (inhibitory) the probability that the cell with which it comes in contact will produce an action potential. Thus, despite the wide variety of synapses, they all convey messages of only these two types, and they are labeled as such. Type I synapses are excitatory in their actions, whereas type II synapses are inhibitory. Each type has a different appearance and is located on different parts of the neurons under its influence. [17]

    Type I (excitatory) synapses are typically located on the shafts or the spines of dendrites, whereas type II (inhibitory) synapses are typically located on a cell body. In addition, Type I synapses have round synaptic vesicles, whereas the vesicles of type II synapses are flattened. The material on the presynaptic and post-synaptic membranes is denser in a Type I synapse than it is in a type II, and the type I synaptic cleft is wider. Finally, the active zone on a Type I synapse is larger than that on a Type II synapse.

    The different locations of type I and type II synapses divide a neuron into two zones: an excitatory dendritic tree and an inhibitory cell body. From an inhibitory perspective, excitation comes in over the dendrites and spreads to the axon hillock to trigger an action potential. If the message is to be stopped, it is best stopped by applying inhibition on the cell body, close to the axon hillock where the action potential originates. Another way to conceptualize excitatory–inhibitory interaction is to picture excitation overcoming inhibition. If the cell body is normally in an inhibited state, the only way to generate an action potential at the axon hillock is to reduce the cell body's inhibition. In this "open the gates" strategy, the excitatory message is like a racehorse ready to run down the track, but first, the inhibitory starting gate must be removed. [18]

    Examples of important neurotransmitter actions Edit

    As explained above, the only direct action of a neurotransmitter is to activate a receptor. Therefore, the effects of a neurotransmitter system depend on the connections of the neurons that use the transmitter, and the chemical properties of the receptors that the transmitter binds to.

    Here are a few examples of important neurotransmitter actions:

      is used at the great majority of fast excitatory synapses in the brain and spinal cord. It is also used at most synapses that are "modifiable", i.e. capable of increasing or decreasing in strength. Modifiable synapses are thought to be the main memory-storage elements in the brain. Excessive glutamate release can overstimulate the brain and lead to excitotoxicity causing cell death resulting in seizures or strokes. [19] Excitotoxicity has been implicated in certain chronic diseases including ischemic stroke, epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington disease, and Parkinson's disease. [20] is used at the great majority of fast inhibitory synapses in virtually every part of the brain. Many sedative/tranquilizing drugs act by enhancing the effects of GABA. [21] Correspondingly, glycine is the inhibitory transmitter in the spinal cord. was the first neurotransmitter discovered in the peripheral and central nervous systems. It activates skeletal muscles in the somatic nervous system and may either excite or inhibit internal organs in the autonomic system. [8] It is distinguished as the transmitter at the neuromuscular junction connecting motor nerves to muscles. The paralytic arrow-poison curare acts by blocking transmission at these synapses. Acetylcholine also operates in many regions of the brain, but using different types of receptors, including nicotinic and muscarinic receptors. [22] has a number of important functions in the brain this includes regulation of motor behavior, pleasures related to motivation and also emotional arousal. It plays a critical role in the reward system Parkinson's disease has been linked to low levels of dopamine and schizophrenia has been linked to high levels of dopamine. [23] is a monoamine neurotransmitter. Most is produced by and found in the intestine (approximately 90%), and the remainder in central nervous system neurons. It functions to regulate appetite, sleep, memory and learning, temperature, mood, behaviour, muscle contraction, and function of the cardiovascular system and endocrine system. It is speculated to have a role in depression, as some depressed patients are seen to have lower concentrations of metabolites of serotonin in their cerebrospinal fluid and brain tissue. [24] which is synthesized in the central nervous system and sympathetic nerves, modulates the responses of the autonomic nervous system, the sleep patterns, focus and alertness. It is synthesized from tyrosine. which is also synthesized from tyrosine is released in the adrenal glands and the brainstem. It plays a role in sleep, with one's ability to become and stay alert, and the fight-or-flight response. works with the central nervous system (CNS), specifically the hypothalamus (tuberomammillary nucleus) and CNS mast cells.

    Neurons expressing certain types of neurotransmitters sometimes form distinct systems, where activation of the system affects large volumes of the brain, called volume transmission. Major neurotransmitter systems include the noradrenaline (norepinephrine) system, the dopamine system, the serotonin system, and the cholinergic system, among others. Trace amines have a modulatory effect on neurotransmission in monoamine pathways (i.e., dopamine, norepinephrine, and serotonin pathways) throughout the brain via signaling through trace amine-associated receptor 1. [25] [26] A brief comparison of these systems follows:

      (LC) projections
    • LC → Amygdala and Hippocampus
    • LC → Brain stem and Spinal cord
    • LC → Cerebellum
    • LC → Cerebral cortex
    • LC → Hypothalamus
    • LC → Tectum
    • LC → Thalamus
    • LC → Ventral tegmental area
      (LTF) projections
    • LTF → Brain stem and Spinal cord
    • LTF → Olfactory bulb
    • anxiety (wakefulness) and working memory (co-regulated by dopamine)
    • feeding and energy homeostasis
    • negative emotional memory (perception of pain) (minor role)
      (VTA) projections
    • VTA → Amygdala
    • VTA → Cingulate cortex
    • VTA → Hippocampus
    • VTA → Ventral striatum (Mesolimbic pathway)
    • VTA → Olfactory bulb
    • VTA → Prefrontal cortex (Mesocortical pathway)
      → Dorsal striatum
      → Median eminence
    • Hypothalamospinal projection
      → Spinal cord
      → Hypothalamus
      (wakefulness)
    • aversion and working memory (co-regulated by norepinephrine)
    • emotion and mood
    • motivation (motivational salience) and control (primary mediator) , orgasm, and refractory period (via neuroendocrine regulation)
      (TMN) projections
    • TMN → Cerebral cortex
    • TMN → Hippocampus
    • TMN → Neostriatum
    • TMN → Nucleus accumbens
    • TMN → Amygdala
    • TMN → Hypothalamus
      (wakefulness)
    • feeding and energy homeostasis
    • learning
    • memory
    • Caudal projections
    • CN → Cerebral cortex
    • CN → Thalamus
    • CN → Caudate-putamen and nucleus accumbens
    • CN → Substantia nigra and ventral tegmental area
    • CN → Cerebellum
    • CN → Spinal cord
    • Rostral projections
    • RN → Amygdala
    • RN → Cingulate cortex
    • RN → Hippocampus
    • RN → Hypothalamus
    • RN → Neocortex
    • RN → Septum
    • RN → Thalamus
    • RN → Ventral tegmental area
      (wakefulness) regulation
    • emotion and mood, potentially including aggression
    • feeding and energy homeostasis (minor role)
    • sensory perception
    • Brainstem nuclei projections
    • BCN → Ventral tegmental area
    • BCN → Thalamus
      (wakefulness)
    • emotion and mood
    • learning
    • motivation (motivational salience) (minor role)

    Understanding the effects of drugs on neurotransmitters comprises a significant portion of research initiatives in the field of neuroscience. Most neuroscientists involved in this field of research believe that such efforts may further advance our understanding of the circuits responsible for various neurological diseases and disorders, as well as ways to effectively treat and someday possibly prevent or cure such illnesses. [41] [ medical citation needed ]

    Drugs can influence behavior by altering neurotransmitter activity. For instance, drugs can decrease the rate of synthesis of neurotransmitters by affecting the synthetic enzyme(s) for that neurotransmitter. When neurotransmitter syntheses are blocked, the amount of neurotransmitters available for release becomes substantially lower, resulting in a decrease in neurotransmitter activity. Some drugs block or stimulate the release of specific neurotransmitters. Alternatively, drugs can prevent neurotransmitter storage in synaptic vesicles by causing the synaptic vesicle membranes to leak. Drugs that prevent a neurotransmitter from binding to its receptor are called receptor antagonists. For example, drugs used to treat patients with schizophrenia such as haloperidol, chlorpromazine, and clozapine are antagonists at receptors in the brain for dopamine. Other drugs act by binding to a receptor and mimicking the normal neurotransmitter. Such drugs are called receptor agonists. An example of a receptor agonist is morphine, an opiate that mimics effects of the endogenous neurotransmitter β-endorphin to relieve pain. Other drugs interfere with the deactivation of a neurotransmitter after it has been released, thereby prolonging the action of a neurotransmitter. This can be accomplished by blocking re-uptake or inhibiting degradative enzymes. Lastly, drugs can also prevent an action potential from occurring, blocking neuronal activity throughout the central and peripheral nervous system. Drugs such as tetrodotoxin that block neural activity are typically lethal.

    Drugs targeting the neurotransmitter of major systems affect the whole system, which can explain the complexity of action of some drugs. Cocaine, for example, blocks the re-uptake of dopamine back into the presynaptic neuron, leaving the neurotransmitter molecules in the synaptic gap for an extended period of time. Since the dopamine remains in the synapse longer, the neurotransmitter continues to bind to the receptors on the postsynaptic neuron, eliciting a pleasurable emotional response. Physical addiction to cocaine may result from prolonged exposure to excess dopamine in the synapses, which leads to the downregulation of some post-synaptic receptors. After the effects of the drug wear off, an individual can become depressed due to decreased probability of the neurotransmitter binding to a receptor. Fluoxetine is a selective serotonin re-uptake inhibitor (SSRI), which blocks re-uptake of serotonin by the presynaptic cell which increases the amount of serotonin present at the synapse and furthermore allows it to remain there longer, providing potential for the effect of naturally released serotonin. [42] AMPT prevents the conversion of tyrosine to L-DOPA, the precursor to dopamine reserpine prevents dopamine storage within vesicles and deprenyl inhibits monoamine oxidase (MAO)-B and thus increases dopamine levels.

    Prevents muscle contractions

    Stimulates muscle contractions

    Increases effects of ACh at receptors

    Used to treat myasthenia gravis

    Prevents muscle contractions

    Causes sedation and depression

    High dose: stimulates postsynaptic receptors

    Enhances attention and impulse control in ADHD

    Blocks voltage-dependent sodium channels

    Can be used as a topical anesthetic (eye drops)

    Prevents destruction of dopamine

    Reduces nausea and vomiting

    Treats depression, some anxiety disorders, and OCD [42] Common examples: Prozac and Sarafem

    Inhibits reuptake of serotonin

    Used as an appetite suppressant

    Stimulates 5-HT2A receptors in forebrain

    Causes excitatory and hallucinogenic effects

    Used in smoking cessation

    Used in research to increase cannabinoid system activity

    Used in research to increase cannabinoid system activity

    Prevents calcium ions from entering neurons

    Impairs synaptic plasticity and certain forms of learning

    Induces trance-like state, helps with pain relief and sedation

    Increase availability of GABA

    Reduces the likelihood of seizures

    Used to study norepinephrine system

    Used to study norepinephrine system without affecting dopamine system

    Agonists Edit

    An agonist is a chemical capable of binding to a receptor, such as a neurotransmitter receptor, and initiating the same reaction typically produced by the binding of the endogenous substance. [46] An agonist of a neurotransmitter will thus initiate the same receptor response as the transmitter. In neurons, an agonist drug may activate neurotransmitter receptors either directly or indirectly. Direct-binding agonists can be further characterized as full agonists, partial agonists, inverse agonists. [47] [48]

    Direct agonists act similar to a neurotransmitter by binding directly to its associated receptor site(s), which may be located on the presynaptic neuron or postsynaptic neuron, or both. [49] Typically, neurotransmitter receptors are located on the postsynaptic neuron, while neurotransmitter autoreceptors are located on the presynaptic neuron, as is the case for monoamine neurotransmitters [25] in some cases, a neurotransmitter utilizes retrograde neurotransmission, a type of feedback signaling in neurons where the neurotransmitter is released postsynaptically and binds to target receptors located on the presynaptic neuron. [50] [note 1] Nicotine, a compound found in tobacco, is a direct agonist of most nicotinic acetylcholine receptors, mainly located in cholinergic neurons. [45] Opiates, such as morphine, heroin, hydrocodone, oxycodone, codeine, and methadone, are μ-opioid receptor agonists this action mediates their euphoriant and pain relieving properties. [45]

    Indirect agonists increase the binding of neurotransmitters at their target receptors by stimulating the release or preventing the reuptake of neurotransmitters. [49] Some indirect agonists trigger neurotransmitter release and prevent neurotransmitter reuptake. Amphetamine, for example, is an indirect agonist of postsynaptic dopamine, norepinephrine, and serotonin receptors in each their respective neurons [25] [26] it produces both neurotransmitter release into the presynaptic neuron and subsequently the synaptic cleft and prevents their reuptake from the synaptic cleft by activating TAAR1, a presynaptic G protein-coupled receptor, and binding to a site on VMAT2, a type of monoamine transporter located on synaptic vesicles within monoamine neurons. [25] [26]

    Antagonists Edit

    An antagonist is a chemical that acts within the body to reduce the physiological activity of another chemical substance (as an opiate) especially one that opposes the action on the nervous system of a drug or a substance occurring naturally in the body by combining with and blocking its nervous receptor. [51]

    There are two main types of antagonist: direct-acting Antagonist and indirect-acting Antagonists:

    1. Direct-acting antagonist- which takes up space present on receptors which are otherwise taken up by neurotransmitters themselves. This results in neurotransmitters being blocked from binding to the receptors. The most common is called Atropine.
    2. Indirect-acting antagonist- drugs that inhibit the release/production of neurotransmitters (e.g., Reserpine).

    Drug antagonists Edit

    An antagonist drug is one that attaches (or binds) to a site called a receptor without activating that receptor to produce a biological response. It is therefore said to have no intrinsic activity. An antagonist may also be called a receptor "blocker" because they block the effect of an agonist at the site. The pharmacological effects of an antagonist, therefore, result in preventing the corresponding receptor site's agonists (e.g., drugs, hormones, neurotransmitters) from binding to and activating it. Antagonists may be "competitive" or "irreversible".

    A competitive antagonist competes with an agonist for binding to the receptor. As the concentration of antagonist increases, the binding of the agonist is progressively inhibited, resulting in a decrease in the physiological response. High concentration of an antagonist can completely inhibit the response. This inhibition can be reversed, however, by an increase of the concentration of the agonist, since the agonist and antagonist compete for binding to the receptor. Competitive antagonists, therefore, can be characterized as shifting the dose–response relationship for the agonist to the right. In the presence of a competitive antagonist, it takes an increased concentration of the agonist to produce the same response observed in the absence of the antagonist.

    An irreversible antagonist binds so strongly to the receptor as to render the receptor unavailable for binding to the agonist. Irreversible antagonists may even form covalent chemical bonds with the receptor. In either case, if the concentration of the irreversible antagonist is high enough, the number of unbound receptors remaining for agonist binding may be so low that even high concentrations of the agonist do not produce the maximum biological response. [52]

    Precursors Edit

    While intake of neurotransmitter precursors does increase neurotransmitter synthesis, evidence is mixed as to whether neurotransmitter release and postsynaptic receptor firing is increased. Even with increased neurotransmitter release, it is unclear whether this will result in a long-term increase in neurotransmitter signal strength, since the nervous system can adapt to changes such as increased neurotransmitter synthesis and may therefore maintain constant firing. [56] [ unreliable medical source? ] Some neurotransmitters may have a role in depression and there is some evidence to suggest that intake of precursors of these neurotransmitters may be useful in the treatment of mild and moderate depression. [56] [ unreliable medical source? ] [57]

    Catecholamine and trace amine precursors Edit

    L-DOPA, a precursor of dopamine that crosses the blood–brain barrier, is used in the treatment of Parkinson's disease. For depressed patients where low activity of the neurotransmitter norepinephrine is implicated, there is only little evidence for benefit of neurotransmitter precursor administration. L-phenylalanine and L-tyrosine are both precursors for dopamine, norepinephrine, and epinephrine. These conversions require vitamin B6, vitamin C, and S-adenosylmethionine. A few studies suggest potential antidepressant effects of L-phenylalanine and L-tyrosine, but there is much room for further research in this area. [56] [ unreliable medical source? ]

    Serotonin precursors Edit

    Administration of L-tryptophan, a precursor for serotonin, is seen to double the production of serotonin in the brain. It is significantly more effective than a placebo in the treatment of mild and moderate depression. [56] [ unreliable medical source? ] This conversion requires vitamin C. [24] 5-hydroxytryptophan (5-HTP), also a precursor for serotonin, is more effective than a placebo. [56] [ unreliable medical source? ]

    Diseases and disorders may also affect specific neurotransmitter systems. The following are disorders involved in either an increase, decrease, or imbalance of certain neurotransmitters.

    For example, problems in producing dopamine (mainly in the substantia nigra) can result in Parkinson's disease, a disorder that affects a person's ability to move as they want to, resulting in stiffness, tremors or shaking, and other symptoms. Some studies suggest that having too little or too much dopamine or problems using dopamine in the thinking and feeling regions of the brain may play a role in disorders like schizophrenia or attention deficit hyperactivity disorder (ADHD). Dopamine is also involved in addiction and drug use, as most recreational drugs cause an influx of dopamine in the brain (especially opioid and methamphetamines) that produces a pleasurable feeling, which is why users constantly crave drugs.

    Similarly, after some research suggested that drugs that block the recycling, or reuptake, of serotonin seemed to help some people diagnosed with depression, it was theorized that people with depression might have lower-than-normal serotonin levels. Though widely popularized, this theory was not borne out in subsequent research. [58] Therefore, selective serotonin reuptake inhibitors (SSRIs) are used to increase the amounts of serotonin in synapses.

    Furthermore, problems with producing or using glutamate have been suggestively and tentatively linked to many mental disorders, including autism, obsessive compulsive disorder (OCD), schizophrenia, and depression. [59] Having too much glutamate has been linked to neurological diseases such as Parkinson's disease, multiple sclerosis, Alzheimer's disease, stroke, and ALS (amyotrophic lateral sclerosis). [60]

    Generally, there are no scientifically established "norms" for appropriate levels or "balances" of different neurotransmitters. It is in most cases pragmatically impossible to even measure levels of neurotransmitters in a brain or body at any distinct moments in time. Neurotransmitters regulate each other's release, and weak consistent imbalances in this mutual regulation were linked to temperament in healthy people . [61] [62] [63] [64] [65] Strong imbalances or disruptions to neurotransmitter systems have been associated with many diseases and mental disorders. These include Parkinson's, depression, insomnia, Attention Deficit Hyperactivity Disorder (ADHD), anxiety, memory loss, dramatic changes in weight and addictions. Chronic physical or emotional stress can be a contributor to neurotransmitter system changes. Genetics also plays a role in neurotransmitter activities. Apart from recreational use, medications that directly and indirectly interact with one or more transmitter or its receptor are commonly prescribed for psychiatric and psychological issues. Notably, drugs interacting with serotonin and norepinephrine are prescribed to patients with problems such as depression and anxiety—though the notion that there is much solid medical evidence to support such interventions has been widely criticized. [66] Studies shown that dopamine imbalance has an influence on multiple sclerosis and other neurological disorders. [67]

    A neurotransmitter must be broken down once it reaches the post-synaptic cell to prevent further excitatory or inhibitory signal transduction. This allows new signals to be produced from the adjacent nerve cells. When the neurotransmitter has been secreted into the synaptic cleft, it binds to specific receptors on the postsynaptic cell, thereby generating a postsynaptic electrical signal. The transmitter must then be removed rapidly to enable the postsynaptic cell to engage in another cycle of neurotransmitter release, binding, and signal generation. Neurotransmitters are terminated in three different ways:

    1. Diffusion – the neurotransmitter detaches from receptor, drifting out of the synaptic cleft, here it becomes absorbed by glial cells.
    2. Enzyme degradation – special chemicals called enzymes break it down. Usually, astrocytes absorb the excess neurotransmitters and pass them on to enzymes or pump them directly into the presynaptic neuron.
    3. Reuptake – re-absorption of a neurotransmitter into the neuron. Transporters, or membrane transport proteins, pump neurotransmitters from the synaptic cleft back into axon terminals (the presynaptic neuron) where they are stored. [68]

    For example, choline is taken up and recycled by the pre-synaptic neuron to synthesize more ACh. Other neurotransmitters such as dopamine are able to diffuse away from their targeted synaptic junctions and are eliminated from the body via the kidneys, or destroyed in the liver. Each neurotransmitter has very specific degradation pathways at regulatory points, which may be targeted by the body's regulatory system or drugs.


    Soma (biology)

    The soma (pl. somas), perikaryon (pl. perikarya), neurocyton, or cell body is the bulbous, non-process portion of a neuron or other brain cell type, containing the cell nucleus. The word 'soma' comes from the Greek ' σῶμα ' , meaning 'body'. Although it is often used to refer to neurons, it can also refer to other cell types as well, including astrocytes, [1] oligodendrocytes, [2] and microglia. [3] There are many different specialized types of neurons, and their sizes vary from as small as about 5 micrometres to over 10 millimetres for some of the smallest and largest neurons of invertebrates, respectively.

    The soma of a neuron (i.e., the main part of the neuron in which the dendrites branch off of) contains many organelles, including granules called Nissl granules, which are composed largely of rough endoplasmic reticulum and free polyribosomes. [4] The cell nucleus is a key feature of the soma. The nucleus is the source of most of the RNA that is produced in neurons. In general, most proteins are produced from mRNAs that do not travel far from the cell nucleus. This creates a challenge for supplying new proteins to axon endings that can be a meter or more away from the soma. Axons contain microtubule-associated motor proteins that transport protein-containing vesicles between the soma and the synapses at the axon terminals. Such transport of molecules towards and away from the soma maintains critical cell functions. In case of neurons, the soma receives a large number of inhibitory synapses, [5] which can regulate the activity of these cells. It has also been shown, that microglial processes constantly monitor neuronal functions through somatic junctions, and exert neuroprotection when needed. [6]

    The axon hillock is a specialized domain of the neuronal cell body from which the axon originates. A high amount of protein synthesis occurs in this region, as it contains many Nissl granules (which are ribosomes wrapped in RER) and polyribosomes. Within the axon hillock, materials are sorted as either items that will enter the axon (like the components of the cytoskeletal architecture of the axon, mitochondria, etc.) or will remain in the soma. In addition, the axon hillock also has a specialized plasma membrane that contains large numbers of voltage-gated ion channels, since this is most often the site of action potential initiation. [4]

    The survival of some sensory neurons depends on axon terminals making contact with sources of survival factors that prevent apoptosis. The survival factors are neurotrophic factors, including molecules such as nerve growth factor (NGF). NGF interacts with receptors at axon terminals, and this produces a signal that must be transported up the length of the axon to the nucleus. A current theory of how such survival signals are sent from axon endings to the soma includes the idea that NGF receptors are endocytosed from the surface of axon tips and that such endocytotic vesicles are transported up the axon. [7]


    Contents

    Complex interconnections of neurons form neural networks, which are responsible for various types of computation in the brain. Neurons receive inputs mainly through dendrites, which play a role in spatio-temporal computation, leading to the firing of an action potential which subsequently travels to synaptic terminals passing through axons. [12] Based on their locations, synapses can be classified into various kinds, such as axo-dendritic synapse, axo-somatic synapse, and axo-axonal synapse. The prefix here indicates the part of the presynaptic neuron (i.e., ‘axo-’ for axons), and the suffix represents the location where the synapse is formed on the postsynaptic neuron (i.e., ‘-dendritic’ for dendrites, ‘-somatic’ for cell body and ‘-axonic’ for synapses on axons). [13] Synapse location will govern the role of that synapse in a network of neurons. In axo-dendritic synapses, the presynaptic activity will affect the spatio-temporal computation in postsynaptic neurons by altering electrical potential in the dendritic branch. Whereas the axo-somatic synapse will affect the probability of firing an action potential in the postsynaptic neuron by causing inhibitory or excitatory effects directly at the cell body. [14]

    Whereas the other types of synapses modulate postsynaptic neural activity, the axo-axonic synapses show subtle effects on the network-level neural information transfer. In such synapses, the activity in presynaptic neurons will not change the membrane potential (i.e., depolarize or hyperpolarize) of the cell body of postsynaptic neurons because presynaptic neurons project directly on the axons of the postsynaptic neurons. Thus, the axo-axonic synapse will mainly affect the probability of neurotransmitter vesicle release in response to an action potential firing in the postsynaptic neuron. Unlike other kinds of synapses, the axo-axonic synapse manipulates the effects of a postsynaptic neuron’s firing on the neurons further downstream in the network. [2] Due to the mechanism of how axo-axonic synapses work, most of these synapses are inhibitory, [6] and yet a few show excitatory effects in postsynaptic neurons. [9]

    The first direct evidence of the existence of axo-axonic synapses was provided by E. G. Gray in 1962. Gray produced electron microscopy photographs of axo-axonic synapses formed on the terminals of muscle afferents involved in the spinal somatic reflex arc in a cat’s spinal cord slices. [15] Later, Gray coined the term ‘axo-axonic’ after getting photographic confirmation from as many as twelve axo-axonic synapses. Within the next two years, scientists found axo-axonic synapses in various other places in the nervous system in different animals, such as in the retina of cats and pigeons, [16] in the lateral geniculate nucleus of monkeys, [17] in the olfactory bulb of mice, [18] and in various lobes in the octopus brain. [19] This further confirmed the existence of axo-axonic synapses in the brain across animal phyla.

    Prior to the discovery of axo-axonic synapses, physiologists predicted the possibility of such mechanisms as early as in year 1935, following their observations of electrophysiological recordings and quantal analysis of brain segments. [20] They had observed inhibitory responses in postsynaptic motoneurons in the slice preparation of the monosynaptic reflex arc. During simultaneous recordings from presynaptic and postsynaptic neurons, the physiologists could not make sense of the infrequent inhibition observed in the postsynaptic neuron, with no membrane potential changes in the presynaptic neuron. At that time, this phenomenon was known as “presynaptic inhibitory action”, the term proposed by Karl Frank in 1959 [14] and later well summarized by John Eccles in his book. [10] After Gray’s finding of the axo-axonic synapse in 1962, scientists confirmed that this phenomenon was in fact due to the axo-axonic synapse present in the reflex arc. [10]

    More recently, in 2006 researchers discovered the first evidence of excitatory effects caused by an axo-axonic synapse. They found that GABAergic neurons project onto the axons of pyramidal cells in the cerebral cortex to form axo-axonic synapse and elicit excitatory effects in cortical microcircuits. [9]

    Below are the brain locations where axo-axonic synapses are found in different animals.

    Cerebellar cortex Edit

    The axo-axonic synapse in the cerebellar cortex originally appeared in one of the drawings of Santiago Ramón y Cajal in his book published in 1909. [21] Later using electron microscopy, it was confirmed that the basket cell axon projects on the axon hillock of Purkinje cells in the cerebellar cortex in cats and other mammals, forming axo-axonic synapses. [5] The first electrophysiological characterization of an axo-axonic synapse formed on Purkinje cells was done in 1963, where the presynaptic basket cell axons were found to inhibit the terminal output of postsynaptic Purkinje cells through the axo-axonic synapse. [22] Network-level study revealed that the granule cells (a.k.a. the parallel fibers) which activated Purkinje cells, also activated the basket cells which subsequently inhibited the effect of Purkinje cells on the downstream network. [23]

    Cerebral cortex Edit

    Axo-axonic synapses are found In the visual cortex (in V1 and V2) in mammals, and have been well studied in cats, rats and primates such as monkeys. [4] [24] [25] [26] [27] The synapse is formed on the initial segments of the axons of pyramidal cells in several layers in the visual cortex. The projecting neurons for these synapses come from various parts of the central nervous system and neocortex. Similarly, axo-axonic synapses are found in the motor cortex, in the subiculum and in the piriform cortex. [4] In the striate cortex, as the Golgi’s method and electron microscopy revealed, as many as five axo-axonic synapses are formed onto a single pyramidal cell. [4] In the cerebral cortex, inhibitory axo-axonic synapses may play a widespread role in network level activity by enabling synchronized firing of pyramidal cells, essentially by modulating the threshold for output of these cells. [27] [4] These synapses are also found on the initial segments of axons in pyramidal cells in the somatosensory cortex, and in the primary olfactory cortex which are found to be the inhibitory kind. [28] [29] Studying the locations of axo-axonic synapses in the primary olfactory cortex, researchers have suggested that axo-axonic synapses may play a critical role in synchronizing oscillations in the piriform cortex (in the olfactory cortex), which aids olfaction. [30] The axo-axonic synapses are also found in the hippocampus. These synapses are found to be formed mainly on principal cells in stratum oriens and stratum pyramidale and rarely on stratum radiatum they commonly receive projections from GABAergic local interneurons. [31] The horizontal interneurons show a laminar distribution of dendrites and are involved in axo-axonic synapses in the hippocampus, which get direct synaptic inputs from CA1 pyramidal cells. [3] Thus, in general, these studies indicate that axo-axonic synapses can provide a basic mechanism of information processing in the cerebral cortex. [32] [30] [31]

    Basal ganglia Edit

    Microscopy studies in the striatum previously suggested rare occurrence of axo-axonic synapses in individual sections. Extrapolations from the topological data suggest much higher counts of such synapses in the striatum where the therapeutic role of the axo-axonic synapses in treating schizophrenia has been postulated previously. [33] In this study, authors examined 4,811 synapses in rat striatum sections, and 15 of them were found to be the axo-axonic synapses. These axo-axonic synapses are formed by dopaminergic inhibitory interneurons (on the presynaptic side) projecting onto the axons of glutamatergic cortico-striatal fibers in the rat striatum. [33]

    Brainstem Edit

    Axo-axonic synapses are found in the spinal trigeminal nucleus in the brainstem. [34] Electron microscopy studies on the kitten brainstem quantified synaptogenesis of axo-axonic synapses in the spinal trigeminal nucleus at different development ages of the brain. Authors identified the synapses by counting vesicles released in the synaptic cleft, which can be observed in the micrographs. Axo-axonic contacts are shown to consistently increase throughout the development period, starting from the age of 3 hours to the age of 27 days in kittens. The highest rate of synaptogenesis is during the first 3 to 6 days, at the end of which, the kitten’s spinal trigeminal nucleus will have nearly half of the axo-axonic synapses present in adult cats. Later, between 16 to 27 days of age, there is another surge of axo-axonic synaptogenesis. [34] Axo-axonic synapses are also observed in the solitary nucleus (also known as nucleus of the solitary tract) uniquely in the commissural portion in the neuroanatomical studies, which used 5-hydroxydopamine to label axo-axonic synapses. Axo-axonic synapses are formed on baroreceptor terminals by the presynaptic adrenergic fibers, and are proposed to play a role in baroreflex. [35]

    Spinal Cord Edit

    Axo-axonic synapses are found in the mammalian spinal reflex arc [36] [37] [38] and in Substantia gelatinosa of Rolando (SGR). [39] In the spinal cord, axo-axonic synapses are formed on the terminals of sensory neurons with presynaptic inhibitory interneurons. These synapses are first studied using intracellular recordings from the spinal motoneurons in cats, and have been shown to cause presynaptic inhibition. [40] This seems to be a common mechanism in spinal cords, in which GABAergic interneurons inhibit presynaptic activity in sensory neurons and eventually control activity in motor neurons enabling selective control of muscles. [41] In efforts to quantify the occurrence of axo-axonic synapses in the SGR region in rats, 54 such synapses were found among the total 6,045 synapses examined. These 54 axo-axonic synapses were shown to have either agranular vesicles or large granular vesicles. [39]

    Vestibular system Edit

    Axo-axonic synapses are found in the lateral vestibular nucleus in rats. Axo-axonic synapses are formed from the small axons of interneurons onto the axon terminals of large axons, which are upstream to the main dendritic stem. [42] Interestingly, the authors claimed that axo-axonic synapses, which are abundant in rats, are absent in the lateral vestibular nucleus in cats. [42] They note that the types of axon terminals identified and described in cats are all found in rats, but the reverse is not true because the axons forming the axo-axonic synapses are missing in cats. These synapses are proposed to enable complex neural computation for the vestibular reflex in rats. [42]

    Hindbrain Edit

    Axo-axonic synapses are found in the mauthner cells in goldfish. [43] [44] The axon hillock and initial axon segments of mauthner cells receive terminals from extremely fine unmyelinated fibers, which cover the axon hillock with helical projections. These helical projections around mauthner cells are also known as the axon cap. The difference between the axo-axonic synapses and other synapses on mauthner cells is that synapses on dendrites and soma receive myelinated fibers, while axons receive unmyelinated fibers. [43] [44] Mauthner cells are big neurons which are involved in fast escape reflexes in fish. Thus, these axo-axonic synapses could selectively disable the escape network by controlling the effect of mauthner cells on the neural network further downstream. Studying the morphological variation of the axo-axonic synapses at the axon hillock in mauthner cells suggests that, evolutionarily, these synapses are more recent than the mauthner cells. Response to the startle can be mapped phylogenetically, which confirms that basal actinopterygian fish, with little to no axo-axonic synapses on mauthner cells, show worse escape response than fish with axo-axonic synapses. [45]

    Neuromuscular junction Edit

    Inhibitory axo-axonic synapses are found in the crustacean neuromuscular junctions and have been widely studied in Crayfish. [6] [7] [46] Axo-axonic synapses are formed on the excitatory axons as a postsynaptic neuron by the motor neurons from the presynaptic side. Motor neurons, which is the common inhibitor in crab limb closers and limb accessory flexors, form axo-axonic synapses in addition to the neuromuscular junction with the muscles in crayfish. [46] These synapses were first observed in 1967, [6] when they were found to cause presynaptic inhibition in leg muscles of crayfish and crabs. Subsequent studies found that axo-axonic synapses showed varying numbers of occurrence based on the location of the leg muscles from the nervous system. For instance, proximal regions have thrice as many axo-axonic synapses than the central regions. [7] These synapses are proposed to function by limiting neurotransmitter release for controlled leg movements. [7]

    An example of the physiological role of axo-axonic synapses, which are formed by GABAergic inhibitory interneurons to the axons of granule cells, is in eliciting spontaneous seizures, which is a key symptom of Intractable Epilepsy. [47] The presynaptic inhibitory interneurons, which can be labeled by cholecystokinin and GAT-1, are found to modulate the granule cells’s spike output. The same cells subsequently project excitatory mossy fibers to pyramidal neurons in the hippocampal CA3 region.

    One of the two leading theories for the pathoetiology of schizophrenia is the glutamate theory. Glutamate is a well studied neurotransmitter for its role in learning and memory, and also in the brain development during prenatal and childhood. Studies of rat striatum found inhibitory axo-axonic synapses formed on the glutamatergic cortico-striatal fibers. [33] They proposed that these axo-axonic synapses in the striatum could be responsible for inhibiting the glutamatergic neurons. Additionally, these dopaminergic synapses are also proposed to cause hyperdopaminergic activity and become neurotoxic for the postsynaptic glutamatergic neurons. [48] This mechanism is proposed to be a possible mechanism for glutamate dysfunction in observed schizophrenia.

    A study on the spinal cord in mice suggests that the sensory Ig/Caspr4 complex is involved in the formation of axo-axonic synapses on proprioceptive afferents. These synapses are formed through projection of GABAergic interneurons on sensory neurons, which is upstream to the motor neurons. In the axo-axonic synapse, expressing NB2 (Contactin5)/Caspr4 coreceptor complex in postsynaptic neurons along with expressing NrCAM/CHL1 in presynaptic interneurons results in the increased numbers of such synapses forming in the spinal cord. [49] Also, knocking out NB2 from the sensory neurons reduced the number of axo-axonic synapses from GABAergic interneurons, which suggests the necessity and the role of NB2 in synaptogenesis of axo-axonic type of synapses. [49] [36]


    How Neurons Communicate - Sept. 27, 2000

    There are more NA+ and Cl- ions outside of the cell than K-, and vice versa.

    There are pumps on the membrane to keep sodium out of the cell. Sodium has a tendency to go into the cell (forced in by diffusion and electrostatic pressure). The other two ions have a balance of forces.

    The action potential is the language the neurons have to talk to each other.

    TODAY'S TOPIC: Now we have this neuron that is "talking" (generating action potential) -How is this translated for another neuron to understand?
    -SYNAPSE

    • terminal button attached to an axon. Inside the axon are microtubules for support.
    • along these microtubules are "balloons" filled with chemicals.
    • these balloons are synaptic vesicles . They're filled with neurotransmitters .
    • inside the terminal button are mitochondria (they produce ATP = energy for the cell)
    • the vesicles concentrate themselves around the pre-synaptic membrane.
    • On the pre-synaptic side of the cleft is the axon.
    • On the post-synaptic side is the dendrite.
    • there is a dark place on the two membranes - it's got special protein molecules (we'll get back to those)
    1. in between terminal buttons and dendrites (on spines or not).
      • AXO-DENDRITIC SYNAPSE
    2. directly on the cell body (skips the dendrite altogether)
      • AXO-SOMATIC SYNAPSE
    3. in some weird cases, the synapse happens to be on another axon.
      • AXO-AXONIC SYNAPSE
    1. action potential generated near the soma. Travels very fast down the axon.
      • -What happens when it reaches the terminal button?
    2. vesicles fuse with the pre-synaptic membrane. As they fuse, they release their contents (neurotransmitters).
    3. Neurotransmitters flow into the synaptic cleft. If the synaptic cleft looks the same on both sides, it's a symmetric synapse. If the sides look different, it's an asymmetric synapse.
    4. Now you have a neurotransmitter free in the synaptic cleft. On the other side are receptors in the membrane. They're like keyholes. They let ions through if and only if neurotransmitters are bound to them! The neurotransmitter binds to the "keyhole" and lets ions through.
      • -These receptors are called ionotrophic receptors. They allow ions through.
    1. - action potential generated.
    2. - vesicle fuses to pre-synaptic membrane.
    3. - release of neurotransmitters.
    4. - neurotransmitters bind to receptors.
    5. - ions flow through the open receptor.

    There is another type of receptor - metabotrophic receptor.
    This type binds the neurotransmitter like the ionotrophic receptor. But instead of letting ions go through directly, the metabotropic receptor activates the second messenger . This messenger goes to open the ion channels.

    The metabotrophic mechanism is slower than the ionotrophic one, but it's very diffused.
    -it will activate ion channels far away from the binding site.

    The ionotrophic mechanism is very quick, but very local (only lets ions through right where the neurotransmitter is located).

    • sodium is allowed through the membrane and into the cell.
    • What happens if you put positive charges inside the cell?
      • depolarization!
      • K+ wants to leave the cell because of diffusion!
      • Because K+ is positive, the inside of the cell becomes less positive (more negative) and there is hyperpolarization of the cell.
      • Hyperpolarization creates an IPSP -- I nhibitory P ost- S ynaptic P otential.
      • You have more chloride outside the cell than inside. It wants to flow in by diffusion.
      • Chloride is negative and makes the voltage inside the cell go down.
      • Again, you get hyperpolarization , and this triggers an IPSP .

      The final polarization the neurotransmitter creates depends on the type of channel it activates.

      This process starts with electrical and ends with electrical signals. In between, there are chemical signals.
      action potential > vesicle fusion > neurotransmitter release > receptor opening > ion flow > EPSP/IPSP

      Why not just "glue" together neurons?

      Drugs work in the chemical stages (talk about that in Ch.4)

      For the postsynaptic neuron to generate an action potential, it needs to receive a stimulus to bring it above the threshold of excitation. It needs a sum of stimuli. (two movies about this on the web)

      • they're destroyed in the synaptic cleft
      • OR they're re-uptaken, (the excess is "sucked up" into the presynaptic site) to be repackaged in vesicles.
      • The effect of cocaine is to block the re-uptake of the neurotransmitter (many effects, including hallucination)
      • neurointegration = the sum of the EPSPs and the IPSPs.
        • EPSPs = positive voltage
        • IPSPs = negative voltage
        1. spatial
          • if a neuron has 4 synapses (2 excitatory, 2 inhibitory), and you have pulses from these at the same time:
            • both excitations at the same time > neuron sees a big voltage (depolarization)
            • both inhibitors at the same time > neuron sees a small voltage (hyperpolarization)
            • one excitor and one inhibitor at the same time > neuron sees the sum = zero!
          • spatial summation - everything happens at the same time and different locations!
        2. temporal
          • Things happen at basically the same place (1 synapse), but different times.
            • if you have 2 action potentials, far apart in time, you'll see 2 "bumps" in the voltage.
            • if you have 2 excitory impulses close to one another in time, there will be summation. A bigger signal will be generated.
            • if you have enough summation in time, you can generate action potential (even with just one synapse receiving/firing action potentials - they fire one right after the other).
            • if you have many inhibitory pulses, you won't get action potential!!
              • The summation "goes the wrong way" - negative!

        In review, spatial summation involves many synapses at one time, and temporal summation involves one synapse at many times.
        In real life, both types of summation are involved with the transmission of action potentials.

        To summarize today's lecture:
        The axon tries to reach the dendrite. Axons are filled with microtubules. On these are vesicles, which travel from the soma to the terminal button. The vesicles sit in the terminal button until an action potential is generated. In vesicles are neurotransmitters. a neuron can have only one kind of neurotransmitter. When action potential is reached, vesicles dock with the presynaptic membrane and fuse with it. They release neurotransmitters into the synaptic cleft. These neurotransmitters bind to receptors on the postsynaptic site. If the postsynaptic cell's receptors are ionotrophic, they allow ions to enter the postsynaptic cell directly. If they're metabotrophic, they activate second messengers to open ion channels. The postsynaptic neuron sums al the action potentials it receives and generates its own action potential on it's own axon, if the voltage of the summed pulses is greater than the threshold of excitation.

        • symmetric synapses usually deal with excitatory neurotransmitters.
        • asymmetric synapses usually deal with inhibitory neurotransmitters.

        Neurotransmitter molecules are recycled back into the presynaptic site or destroyed by chemicals.
        But sometimes, you have receptors in the presynaptic site. These are autoreceptors. The goal of autoreceptors is to modulate the production of neurotransmitters on the presynaptic side.