Essay: Synaptic Transmission

Synaptic Transmission is a mechanism of communication between neurons in the nervous system of organisms. This mechanism of transmission is an important as it helps to regulate parasympathetic and sympathetic actions of the peripheral nervous system (PNS) and also underlies the modulation and regulation of cognition, mood, learning, and memory within the central nervous system (CNS). Synaptic transmission involves two types of synaptic modalities called electrical synapses and chemical synapses. While this review will touch on electrical synaptic transmission the focus will largely be on chemical synaptic transmission.
Electrical Synapses
Electrical synapses permit passage of currents, ions, and small molecules from the presynaptic terminal to the postsynaptic terminal through gap junctions. Gap junctions are intercellular specialization complexes that are comprised of connexons. Each connexon are comprised of six connexins, which are individual protein subunits, and together two connexons form a gap junction. There are a wide variety of connexin subunit types which allow gap junction to have a diverse range of functional properties such as pH sensitivity, Ca2+ sensitivity, membrane voltage sensitivity, different cell types, and direction of transmission (unidirectional or bidirectional). Gap junctions differ from other traditional membrane channels in that they cross two membranes which connect the cytoplasm of one cell to the cytoplasm of another, they also require proteins from two different neurons to form cell-cell channels, and the channels of gap junction are much wider in diameter than ion channel pores. Gap junctions permit the transmission of ions, ATP, small metabolites, and second messenger molecules. Due to the direct membrane connections, a result of the gap junction, transmission from one neuron to another is extraordinarily rapid due to instantaneous passive current flow. A general consensus for the importance of these synapses is that they allow electrical activity among many neurons to be synchronized, allowing cells to fire action potentials in unison, resulting in release of molecules to stimulate other cellular mechanisms rapidly and with ease. Electrical synapses are also coincidence detectors since localized changes in membrane potential can be detected be other neighboring cells which in turn allows for coordinated cellular activity. Many interneurons of the nervous system, such as inhibitory interneurons, are coupled together by electrical synapses, since interneurons are important in quickly regulating local networks of neurons. Different structures in the brain that utilize electrical synapses consist of the retina, olfactory bulb, cerebral cortex, hippocampus, suprachiasmatic nucleus, hypothalamus, the inferior olive, the brainstem, and the spinal cord motor and sensory systems. Electrical synapses are shown to be capable of plasticity as they are able to modify their coupling strength in response to different physiological changes and conditions, allowing for neural networks to reconfigure themselves. Though this brief review sheds some light on the functional mechanisms of electrical synapses, the entire scope of the information is still incomplete and poorly understood making it difficult to explain the specific roles these synapses play in the nervous system. Growing evidence now suggests that synaptic transmission involves the coupling of electrical synapses as well as chemical synapses as both contribute or underlie different aspects of behavior, learning and memory, fine motor control, as well as information processing.
Chemical Synapses
Unlike electrical synapses, chemical synapses have been studied rather extensively and a great deal of information is available. Chemical Synapses, similar to electrical synapses, are sites of communication between two neurons. The difference is that chemical synapses don’t have two membranes connected directly together through gap junctions but rather the presynaptic terminal releases neurotransmitters across a region of space, called the synaptic cleft, to activate receptors on the postsynaptic terminal. Chemical synapses rely on more complex mechanistic criteria such as (a) the synthesis of neurotransmitters; (b) the storage of neurotransmitters in vesicles, (c) regulated release of the transmitter from vesicles by an action potential and calcium presence; (d) presence of postsynaptic receptors that are bound by specific neurotransmitters; (e) and mechanisms that terminate the activation of the neurotransmitter. Chemical synapses meet these criteria through specific processes which are underlie aspects of neural plasticity and learning, cognition, and memory. Each of these criteria will be expanded on in further detail below.
Neurotransmitter Synthesis
Neurotransmitters are specific ligands that target specific receptors when released. To be considered a neurotransmitter, a molecule must (a) be present at the presynaptic terminal; (b) be released; (c) and activate postsynaptic receptors. The six families of neurotransmitters are acetylcholine, amino acids, biogenic amines, purines, peptides, and “other”. The acetylcholine families consist of the molecule acetylcholine. Amino acid family consist of two categories excitatory (glutamate and aspartate) and inhibitory (GABA and glycine) amino acids. The purine family consists of ATP which can be considered a non-traditional neurotransmitter. Biogenic amines are separated into three classes called catecholamine’s (Dopamine, Norepinephrine, and Epinephrine), indoleamine (Serotonin), and imidazoleamine (Histamine). Peptide transmitters consist the classes brain-gut peptides, opioid peptides, pituitary peptides, hypothalamic-releasing peptides, and a miscellaneous class of peptides. The “other” family consists of non-traditional neurotransmitters such as endocannabinoids and nitric oxide. These non-traditional neurotransmitters act in a retrograde fashion, meaning they diffuse from the postsynaptic membrane to activate receptors on the presynaptic membrane to. For the sake of this review non-traditional neurotransmitters, the purines and “other”, won’t be explained in detail. A better way to organize these families of neurotransmitters is to categorize them as small-molecule transmitters (Biogenic Amines, Amino Acids, and Acetylcholine) and large-molecule transmitters (Peptides) as these new categories follow similar synthesis pathways.
Small-molecule transmitters are products of other molecules synthesized through the use of enzymes. Precursors of neurotransmitters are generally made available through specific transporters that bring them into the cell or made available by breakdown of other available molecules. Enzymes important for the synthesis of neurotransmitters are generally made in the cell soma and then transported down the axon and made available in the presynaptic terminal. Acetylcholine is a derivative of choline and acetyl coenzyme A synthesis by choline acetyltransferase enzyme. Tyrosine hydroxylase is an enzyme that converts tyrosine to DOPA, DOPA is turned into dopamine by DOPA-decarboxylase, dopamine to norepinephrine by dopamine-Beta-hydroxylase, and norepinephrine to epinephrine by phenylethanol amine N-methyl-transferase. Histamine is made from histidine by histidine decarboxylase. Tryptophan is converted to 5-hydroxytryptophan by tryptophan-5-hydroxylase which is further modified into serotonin by aromatic L-amino acid decarboxylase. Glutamate is synthesized from glutamine by glutaminase and GABA is synthesized from glutamate by glutamic acid decarboxylase. Glycine is synthesized from serine by serine hydroxymethyltransferase. These small-molecule transmitters are synthesized at the synaptic terminal where the rate of transmitter synthesis can be more readily regulated by influxes of calcium which interact with second messengers such as adenylyl cyclase. Adenylyl cyclase then increase production of cyclic AMP which then activates protein kinases that phosphorylate enzymes, increasing the rate at which small-molecule transmitters are synthesized.
Most large-molecule transmitters, neuropeptides, follow the same production pathway as proteins and are also hormones. mRNA is transcribed from DNA, transported out of the cell, and the mRNA is then translated into a specific sequence of amino acids called pre-propeptides. Pre-propeptides contain many peptides and are then processed into pro-peptides in the Golgi apparatus. In the Golgi apparatus pre-propeptides have their golgi retention signal cleaved which signals packaging and export out of the Golgi apparatus. Once in vesicles, they travel from the cell body, the soma, and undergo post translational modifications. These modifications (proteolytic cleavages, glycosylation, phosphorylation, etc.) breakdown propeptides into active peptides which are then ready for release.
Vesicle Loading and Release
Vesicles loading is the next stage in synaptic transmission. When the vesicles containing peptides reach the synaptic terminal they are docked and ready for release. Peptide containing vesicles are called dense core vesicles and are generally docked further away from the synapse. Small-molecule transmitters are loaded into vesicles using specific transporters on the vesicles themselves that are energy requiring transporters and are referred to as small clear core vesicles. Monoamines utilize vesicular monoamine transporters, glutamate utilizes vesicular glutamate transporters, and GABA/glycine utilize vesicular inhibitor amino acid transporters. Small clear core vesicles are docked and stored closer to the active zone of the synapse. Small-molecule transmitters can also be stored in the dense core vesicles alongside peptides. Vesicles are linked together and tethered to the vesicle pool by a protein called synapsin, which is similar to other cytoskeletal proteins. Vesicles also contain a large number of different proteins in their membrane that help to regulate release and other function. There are three types of vesicle pools, the readily releasable pool, the reserve pool, and the recycling pool. Vesicle release from these pools are dependent on intercellular calcium levels and the strength of electrical stimulation.
Vesicle release is instigated by depolarization of the presynaptic membrane which then opens voltage gated calcium channels allowing an influx of Ca2+ ions. Vesicles follow a specific pathway for release called the synaptic vesicle cycle. The first part of the cycle, as explained above, involves vesicle components being trafficked to the synapse where they are put together and then loaded with neurotransmitters by a neurotransmitter transporter and ATPase proton pump. The next part of the cycle, called docking, involves vesicles being anchored to cytoskeletal proteins by synapsin. Next the vesicles are primed which involves the formation of SNARE complexes which allow vesicles to be available to fuse to the membrane rapidly. These SNARE complexes are created through synaptobrevin, syntaxin, and SNAP-25 proteins that coil together to bring the vesicle closer to the membrane. When an action potential travels down the axon, voltage gated calcium channels open allowing calcium levels within the cell reach appropriate levels, calcium then interacts synaptotagmin, a calcium sensor, that triggers exocytosis to begin. The SNARE complex then allows the vesicle to start fusing to the presynaptic membrane and the contents of the vesicles are released into the synaptic cleft. Next vesicle endocytosis begins and is moderated by clathrin. Clathrin acts as a scaffolding which pinch the membrane and allows for the vesicle to be reconstituted. Another protein called dynamin allows for the vesicle to be dissociated from the membrane. The clathrin coat is then removed from the vesicle and the vesicle goes to the recycling pool where it is reloaded and clustered with other vesicles. Though the synaptic vesicle cycle does explain release of both kinds of vesicles there are other requirements that need to be met which differ between small clear core and dense core vesicles. Small core vesicle release is rather easy to instigate as they only require low frequency stimulation for release which raises calcium levels close to the membrane. Large dense core vesicles require high frequency stimulation which increases intracellular calcium levels even more allowing for release. Small clear core vesicles can also be co-released with large dense core vesicles.
Receptor Binding
Once the neurotransmitter is released the from the presynaptic density by exocytosis, it is free to travel across the synaptic cleft, a region of space between the pre- and post- synaptic terminals and activate receptors. Signal amplification and signal computation are other advantages of chemical synapses. Signal amplification is when one action potential can innervate many other postsynaptic targets, whereas signal computation is when a single target can be innervated by many excitatory and inhibitory synapses. Signal computation allows the target cell to sum the incoming excitatory and inhibitory signals which in turn will decide whether the summation is strong enough to fire an action potential.
There are two types of receptors, ionotropic and metabotropic. Ionotropic receptors are ligand gated ion channels. They require a specific ligand to bind to them which changes the channels conformation and opens the channel, permitting entrance of ions such as sodium, potassium, calcium, and/or chloride. The selectivity of the ion channels allows for excitatory or inhibitory post synaptic potentials that modulates whether the postsynaptic is going to fire an action potential. While most ionotropic receptors are named after the specific neurotransmitter that binds to them, glutamate activates AMPA, NMDA, and kainite receptors. Neurotransmitter can activate excitatory receptors which allow for membrane depolarization which attenuates action potentials, or they can activate inhibitory receptors which hyperpolarize the membrane, repressing action potentials stimulation.
Different metabotropic receptors types bind specific neurotransmitters, activate a series of intracellular mechanisms, which then activate different targets such as other ion channels or intracellular targets. All metabotropic receptors are G protein-coupled receptors. Different classes of G proteins exist such as Gi, Gs, and Gq. Gq activates phospholipase c which hydrolyzes PIP2 into DAG and IP3. DAG activates PKC which phosphorylates different targets while IP3 activates IP3 receptors on the endoplasmic reticulum that increase intracellular calcium levels. Gi (G-inhibitory) and Gs (G-stimulatory) decrease or increase adenylyl cyclase activity, respectively, which then causes a cascade of interaction that leads to decreased or increased PKA activity. PKA is a protein kinase important in phosphorylating other cellular target regulating their activity. Unlike ionotropic receptors, metabotropic receptors have wide spread targets and their effects last longer. Another function of metabotropic receptors is modulation of potassium channels, changing how sensitive the membrane is to depolarization.
Activation of postsynaptic receptors by neurotransmitters can regulate different forms of long term potentiation/depression through different mechanistic pathways. Long term potentiation leads in an increase in synaptic strength and long-term depression leads to weakening of synaptic strength. Early long-term potentiation involves the activation of protein kinases and posttranslational changes to ion channels, whereas late phase long term potentiation involves CREB dependent gene expression and synaptic growth. For instance, NMDA activation can lead to long term potentiation when calcium enters the cell through NMDA receptors it binds to calmodulin, which in turn activates calmodulin kinase 2 and PKC which phosphorylate substrates causing insertion of AMPA receptors into the membrane. Long term depression can result when calcium enters through the NMDA receptors, binds to calmodulin, activates phosphatases such as calcineurin (protein phosphatase 2B), and phosphatases dephosphorylate substrates leading to internalization of AMPA receptors.
Signal Termination
Finally, the actions of the neurotransmitters must be terminated. Termination of neurotransmitters can be caused by (a) diffusion of the neurotransmitter away from the cleft; (b) transportation back into the presynaptic neuron; or (c) be degraded by enzymes.
Monoamine neurotransmitters are transported back into the presynaptic terminal through specific transporters, such as the specific serotonin transporter, dopamine transporter, and the norepinephrine transporter. Once back inside the cell monoamines are degraded by monoamine oxidase in mitochondria or by catechol-o-methyltransferase in the cytoplasm.
Glutamate is taken into glial cells or the neuron through excitatory amino acid transporters. Inside the glial cells glutamate is degraded into glutamine, transported into the extracellular space by system N transporter 1, and then glutamine is transported into the neuron through system A transporter 2. GABA is cleared from the cleft and transported into glial cells or the neuron through GABA transporters. The GABA pathway into glial cells is similar to the glutamate path but it isn’t converted back to glutamine. Glycine is cleared into the neuron or glial cells through glycine transporters. Acetylcholine is degraded into acetate and choline by acetylcholinesterase. The byproduct, choline, is then transported back into the neuron through choline transporters. Once the neurotransmitters are degraded and transported back into the neuron they can be resynthesized and packaged back into vesicles to be released again.
This review is only meant to briefly explain different forms of synaptic transmission and what mechanism underlie both electrical and chemical synapses. While electrical synaptic transmission is quick and chemical synaptic transmission is slower, both have similar result in that transmission in these synapses lead to changes in cellular activity by affecting different targets. The only thing that differs is the mechanism in which each utilizes to affect distant targets. Although information on electrical synapses isn’t as complete as chemical synapses, this doesn’t mean one mode of transmission is more complex. Growing interest of electrical synapses will eventually shed light on mechanism that are still poorly understood.