So far, we understand that in-between two neurons (that are sufficiently near each other) is a small space called a synapse. The presynaptic neuron tells the sack-like vesicles that contain the neurotransmitters, to empty them into the synapse. These float around, many finding their way across the synapse to postsynaptic receptors, which are located on dendrites. Neurotransmitters fit into receptors much as the same way that key fits into a lock.

Basic neuroscience holds that once this chemical “key” fits into the receptor “lock”, an electrical charge is created at that point. This charge makes its way down this post-synaptic cell, through the cell body and axon of the next neuron, which in turn secretes chemicals into another synapse. The message is propagated as these chemicals find their way to receptors, which activate neurons, causing a charge to run through them, the release of neurotransmitters into another synapse, and so on.

 

The below image serve to better communicate the chain-reaction of electrochemical nature, the means by which neurons talk to each other.

As we recall, our leftmost image depicts ionotropic receptors, or, ligand-gated ion channles, which open or close of a channel, and the flow of ions into the postsynaptic neurons.

The image below, and that of below-right, depict a string-like thread passing several times across a cellular domain. The ligand binding domain is the place of a metabotropic receptor, or, g protein-coupled receptor. Once the ligand, or, “key”, fits into the receptor, it “pulls” on the string-like receptor, which causes changes to the neuron downstream, through what’s called the second-messenger system. Alternatively, the inside part of this string could open an ion channel further along the cell membrane, from the inside.

Finally, there are two more forms of receptors

 

Kinase-linked receptors are particularly important because they can change the activity of genetic agents in neurons, and seem to play a role in the production of large neurotransmitters, such as opioids and other peptides, which cause volume neurotransmission: (activity far away from the neuron of release). They alseo participate in the immune system response (governed by cytokines).

Nuclear receptors additionally are involved in cellular transcription, and, when activated, do so in the deepest part of the cell nucleus. These receptors are heavily involved in hormone activity, furthermore.

 

This next section will begin by detailing this process in more electrophysiological detail.

The membrane potential is defined as the measure of difference in electrical charge between the inside of the neuron, and the outside, measured in millivolts. So a membrane potential of -90 would mean that the charge in the neuron is 90mv fewer than outside of it.

In order to send a message from the dendrites of a neuron, all the way to it’s terminal button, the membrane potential must reach a certain level. It does this through psps – the flow of ions through channels into, or out of, the neuron.

  • When a neurotransmitter fits into a postsynaptic receptor, it generates a post-synaptic potential, or, PSP, at that receptor spot
    • Ion channels open or close, affecting the membrane potential of the neuron
    • Excitatory psps (EPSPSs)raise the membrane potential
      • The neuron becomes more depolarized, the inside charge increasing
      • The next neuron is more likely to fire
      • Sodium ions (Na+2) moving into the neuron through a channel
    • Inhibitory psps (IPSPs) lower the membrane potential
      • The charge inside the neuron decreases, hyperpolarizing it
      • The next neuron is less likely to fire
      • Chlorine ions (Cl-) moving into the neuron via channel
      • Potassium ions (K+) moving out of the neuron via channel

Firstly, a sole neurotransmitter or psp almost never activates a postsynaptic neuron by itself. There are two ways that psps can create a charge strong enough to change neuronal activation.

  1. Temporal summation is when psps rapidly propagateat one receptor site
  2. Spatial summation is when multiple psps happen at once, but at different receptor sites.

When a neuron is at rest, it is in a state of resting membrane potential – measured electrically – of about -70mv. This means that the environment inside the neuron has a -70mv charge relative to the outside. Things are in stasis. To get that neuron to fire, there has to be (temporally and/or spatially) enough EPSPs depolarizing the neuron at the axon hillock. Once achieved, the threshold of activation is met. Generally, this charge is -60mv, 10mv more than the resting potential of -70mv.

So when a charge of -60mv reaches the axon hillock, the threshold being met, an action potential almost immediately takes place.

  1. Voltage-gated (controlled electrically, as opposed to by a ligand) sodium ion channels open
  2. Sodium ions enter, depolarizing the immediate vicinity
  3. The depolarization charge also spreads a bit beyond the channel
  4. The original sodium ion channel closes
  5. A voltage-gated potassium channel around that sodium ion channel opens in a repolarization effort, though it doesn’t destroy the whole depolarization signal
  6. The potassium ion channel closes
  7. The original sodium ion charge has diffused to another voltage-gated sodium ion channel, which opens, creating another influx of sodium ions, and depolarization of that general area
  8. This process continues until the charge has reached the axon button

In this process, their is a dynamic called the absolute refractory period, a period of time during which the neuron cannot under any circumstance fire again. This is when the ion channels have closed. Shortly after sodium channels close, potassium channels open in an attempt to repolarize the neuron, to move it back to resting potential. When potassium channels are open, another neural impulse could conceivably take place, but it would have to be much stronger than the initial charge; this is called the relative refractory period.

Despite potassium channels, the charge elicited by the sodium spreads down the axon. It could be said to “jump” to gaps, which are termed nodes of ranvier, spaces on the axon that that are not myelinated, and which voltage-gated ion channels are present.

Here’s another way of saying it…

  1. If the charge has reached the axon hillock, the charge has also reached one of many (sodium) voltage-gated ion channels that span the axon
  2. So that charge causes the sodium ion channels to open, causing sodium cations (Na+2) to enter the neuron, and depolarize that intracellular area
  3. This positive charge depolarizes the area around the voltage-gated sodium ion channel, creeping a bit down the axon
  4. The sodium channel closes
  5. A voltage-gated potassium channel around the recently opened sodium ion channel opens up, repolarizing that space by a wave of pottasium cations (K+) exiting the neuron
  6. The pottassium, ion channel closes
  7. However, a positive charge has already made its way down the axon a bit and past the domain of that potassium ion channel
  8. And when the charge of the initial sodium influx reaches a spot along the axon that isn’t covered in myelin sheath (a node of ranvier), another voltage-gated sodium channel opens, repeating the whole process 
  9. In this manner, the positive (depolarization) charge “jumps” from node of ranvier, to node of ranvier, until it reaches the end of the axon, the terminal button/axon terminal
  10. When the charge reaches the terminal button, voltage-gated calcium channels on the button open, creating an influx of calcium cations (Ca+2)
  11. This causes the vesicles to fuse with the neuronal membrane, and release neurotransmitters into the synapse

We know all these terms, and recognize the depiction below

PSPs become weaker as they travel, have an effect in proportion to their charge, and travel very fast. This is in contrast to action potentials.

We’ve also honed in on many different neurotransmitters, and what physiological and psychological effects they produce when binding to receptors and some of the subtypes/subunits of those receptors. For example, the 5-HT (serotonin) subtype 1 receptor helps control habits like eating, inner environments like body temperature, and mood states such as anxiety and depression.

We’ve also gone over how chemicals can also be classed based on the specific manner that they change activity, the way that they interact with receptors. For example, partial agonists keep the activation of a receptor within bounds, and antagonists occupy a receptor, which prevents agonists from activating it.

Let’s zoom in on ionotropic neurotransmission:

Yet, things are more complicated. A bit of chemistry and some more biology is in order.

First of all, there exist neuronal connections called gap junctions. There is no synaptic connection. Messages are purely electrical in nature. The gap junction channel are called connexons.

Also, the brain has other non-traditional connections, ones that break the norm of the axon terminal reaching a charge that makes it release chemicals that then fit into receptors on another neurons dendrite. By this its meant that axo-axo, axo-somatic, and dendritic-dendritic neural connections , do exist.

In a similar light, not all neurotransmitters are are sent from the terminal button, across the synapse, then fit into their receptor before being pumped into their presynaptic neuron and/or destroyed by enzymes. Neurotransmitters that act on a relatively wide area, past which they were released, participate in what’s called volume neurotransmission. This wide-ranging effect is usually seen in peptides (chains of amino acids) and other large neuroactive chemicals. But the monoamine neurotransmitters (serotonin, dopamine, epinpehrine, norepinpehrine) seem to be an exception in that they affect the brain widely, but are “small’ neurotransmitters, variations on amino acids.

One last unusual manner in which the brain functions is through something called visocity. This means that neurotransmitters, as they travel along the axon to the button, leak out as a result of bulges

Above was most of the material that breaks the rules…

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Source

Per above, there is one more type of receptor that hasn’t been discussed. This is the G-protein coupled receptor type.

As can be seen below, when the action potential reaches the terminal button (the axon terminal), calcium channels open, and calcium cations invade. This causes the vesicles (which hold neurotransmitters) to fuse with the presynaptic membrane, and release stores of neurochemicals into the synapse.

Regarding G-protein coupled receptors:

Reuptake pumps: proteins that lie on the presynpatic membrane, and through a chemical bond, facilitate passage of neurotransmitters back into the presynpatic neuron; blocking this pump, which kinds exists for all of the monoamines, is the main psychiatric target for depression.

Neurotransmitters roughly follow this cycle

  1. Creation (a large protein/peptide at the some, or a small neurotransmitter at the button)
  2. Enough of an electric charge (through spatial and temporal summation) meets the axon hillock
  3. A chain-reaction of sodium and potassium depolarity reaches the terminal button
  4. Calcium channels open, causing vesicles to empty neurotransmitters into the synapse, until autoreceptors, lining the periphery of the presynaptic membrane, become saturated, telling the neuron to release no more.
    1. The reuptake pump (also called transmembrane transporter) leeches back an appreciable amount of neurotransmitters from the synapse
    2. Once in the presynaptic neuron again, metabolism by the inner-synaptic monoamine oxidase A (MAOB) and/or monoamine oxidase B (MAOB, may ocurr, as they hook on to neurotransmitters. MAOI is the mechanism by which antidepressants for treatment-resistant people work
    3. Another possibility when back in the presynaptic neuron, is being repackaged by one of two kinds of vesicular monoamine transporters (VMAT) back into vesicles, to be released at a later time

Also what can be seen below are sodium channels on the post-synaptic membrane.

chemical-synapse

As noted above, another kind of receptor exists, the G-protein coupled receptor. Instead of allowing passage of ions into the postsynaptic neuron, when a ligand binds to its receptor in this case, it tugs what can be thought of as a string; the ligand is termed the first messenger. Once it binds, a subunit (a part of) the G-protein inside the postsynaptic neuron, the second messenger, breaks away; once done, it either gravitates along the edge of the postsynaptic neuron and binds to an ion channel, or it makes its way to the cell nucleus and interacts with the way by which the nucleus produces proteins, possibly changing gene expression.

A bit more about neuronal structure and function.

Mitochondria are heavily involved in energy production, ATP. Two of the three enzymes that break down monoaminergic compounds MAO-B and MAO-A), are found on the mitochondria. The third is catachol-o-methyltransferase (which of course breaks down catecholamines).

The golgi apparatus packages neurotransmitters into vesicles.

The endoplasmic reticulum serves two functions.

  1. The smooth portions have ribosomes on them, which create proteins used to conceive of large neurotransmitters (peptides), which are then carried to the axon terminal through microtubules, when their release is called for. In contrast, small neurotransmitters (such as amino scids) are conceived at the terminal button, very close to where they will eventually be realeased.
  2. The rough parts are involved in lipid production

The cell nucleus is responsible for neuronal DNA, the specific code of the neuron. Second-messengers elicited by ligands of G-protein coupled receptors, oftentimes lead to transcription factor activation within the nucleus, changes its very genetic makeup.

Cytoplasm is surrounding cell fluid that belongs to a particular structure within the cell (each cellular structure is an organelle)

Cytosol is cell fluid that does not belong to, in essence isn’t attracted to, any particular organelle

Telodendria are the parts of axons that have terminal buttons (axon terminals)

Blausen_0657_MultipolarNeuron

What we’ve been describing up to this point, in terms of neurotransmission, is anterograde transport, the normal way by which it occurs. Some neurotransmitters, such as cannabinoids and NO, operate by retrograde transport, which acts to produce an inhibitory mechanism.

Lastly, we’ll discuss neurotrophins. These are chemicals, proteins, that aid in the maintenance, and repair, of neurons, and stimulate the production of dendrites. They can stop mitochnodrial and somatic- mediated programmed cell death (apoptosis). Summarily, they mediate neuronal plasticity and intracellular transcription (altering the genetic code of the cell).

However, in some cases neurotrophins act to destroy nerve cells, ones that the brain doesn’t deem useful enough to exist. Thus, the brain becomes more efficient. This process, synaptic pruning, largely happens as we grow into adults, as we are born with 150 billion neurons, but end up with about 100 billion.

The most abundant neurotrophin in the central nervous system, is brain-derived neurotrohpic factor (BDNF). Others include nerve growth factor (NGF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), neurotrophin-5 (NT-5), and neurotrophin-7 (NT-7). The former four of these are said to compose the NGF family. Neurotrophins bind to Trk (tropomyocin receptor kinase) receptors, and to a receptor dubbed P75, as seen below.

 

It’s been proposed that neurotrophic activity is behind the antidepressant effects of SSRIs. People with depression have been documented as having lower levels of BDNF. Postmortem brain samples of people with diagnosed clinical depression also show abnormally low levels of BDNF, as well as do those of suicide victims. BDNF has been shown to promote the creation, function, and repair of 5-HT (serotonergic) neurons. As antidepressants largely function to facilitate significant neurogenesis in the dendate gyrus region of the hippocampus, that function is dependent on BDNF and other neurotrophins. Clear documentation of almost every antidepressant shows it to increase the activity of BDNF. However, consistent with the theory of recovery, therapy is essential to optimize this process.

Here we have an advanced depiction of how BDNF can differentially affect a cell.

Below is a quite complicated image, more than I’d be able to explain at this point. We see the detailed intracellular effects metabotropic, iontropic, and neurotrophic, receptor binding.

The image also depicts the various receptor sub-families (as well as individual receptor subtypes and subunites), based on the effects when a given neurotransmitter binds to it. For instance, DA (dopamine) 2,3, and 4 receptor subtypes produce similar effects when activated. DA 1 and 5 receptor subtypes produce significantly different effects (when activated) than DA 2,3, and 4. Both of these are types dopamine receptors, but they’re divided into two based on effect. And then, of course, they’re further divided into five.

Similarly, 5-HT (serotonin) receptor suptypes 1,4,5,6, and 7, are fairly similar. 5-HT2 has its own class. 5-HT3 is much more different because, unlike the two aforementioned sub-families, it is an ionotropic subunit.

Here we have a decent juxtaposition of ionotropic (ligand-gated ion channels) and metabotropic (g-coupled protein receptors), and how chemicals interact with both types of receptors:

GABA, glutamate, and acetylcholline, also bind to both metaboptropic and ionotropic receptor regions – a much more even split than 5-HT.

The image below is an impressive compendium of all of the neurotransmitters, their receptors, and furthermore activity caused through second-messenger systems and all the the eventual ends of these processes, of just about all of the activity that can go on in a neuron.

Sources: Dr. Kevin Davis, Biopsychology, Abnormal Psychology: An Integrative Approach, faculty.washington.edu, http://pharmrev.aspetjournals.org/content/pharmrev/60/3/358/F2.large.jpg?width=800&height=600&carousel=1, Stahl’s Essential Psychopharmacology, http://www.prospecbio.com, Brain-derived neurotrophic factor in mood disorders and antidepressant treatments, https://www.ebi.ac.uk, http://www.pnas.org/content/112/51/15737.short