How Neurons Communicate to Each Other at a Chemical Synapse?

Introduction The discovery of how the nervous system communicates to each other at the cellular level is one of the most astonishing works done by the neuroscientists. Based on the process of chemical neurotransmission (communication of nervous system), drugs that treat neurological diseases, like insomnia, depression, eating disorder, and neurodegenerative diseases, have been developed. The following discussion proposes the most recent theory of the process of chemical neurotransmission between presynaptic and postsynaptic neurons. This document will clarify the process of transmitting chemical molecules from the presynaptic to the postsynaptic neuron for students who are currently taking college level neurobiology or psychology classes. The first topic focuses on the presynaptic neurons and describes the five steps of cycle of synaptic vesicles carrying the chemical neurotransmitters for transmission. The second topic focuses on the postsynaptic neuron and introduces two distinct receptors: Ionotropic and Metabotropic receptors. Presynaptic Neurons: Cycle of synaptic vesicles At chemical synapses there is a gap between presynaptic and postsynaptic neurons, called synaptic gap (or synapse). Generally chemical synaptic transmission depends on the diffusion of a chemical neurotransmitter across the synapse. Thousands of neurotransmitters are packaged inside a synaptic vesicle and released through the process known as Exocytosis. Five steps of the cycle of synaptic vesicles before neurotransmitters leave the presynaptic neuron will be discussed in a chronological order.

Figure 1 The Synaptic Vesicle Cycle http://www2.tau.ac.il/InternetFiles/Researchers/images/82_Ashery_Uri.jpg

1) Trafficking of synaptic vesicles toward the terminal membrane The transportation of neurotransmitters is carried out by synaptic vesicles. Neurotransmitters reserved in the presynaptic neuron enter into the empty vesicles through active transport, which provides energy to go against the concentration gradient. When synaptic vesicles are filled with neurotransmitters (chemical molecules), they cluster in the nerve terminal to dock at the active zone of the presynaptic membrane. 2) Docking process of synaptic vesicles to the terminal membrane Filled vesicles dock at the active zone of the presynaptic neuron, preparing to release thousands of chemical molecules to the synaptic gap. The docking of vesicles is done by the help of the synapsins. Synapsins are peripheral membrane proteins that are bound to the cytoplasmic surface of synaptic vesicles, which are utilized as a restraint and mobilization of vesicles. After attaching to the active zone, synaptic vesicles undergo an ATP-dependent priming reaction, which enables the vesicle to fuse with the terminal membrane when triggered with calcium ion signal. 3) Fusion of synaptic vesicles and the terminal membrane During a presynaptic action potential, voltage gated Ca2+ channels at the active zone opens and allows Ca2+ to enter the presynaptic terminal. The gradual increase of Ca2+ concentration triggers a reaction that causes the vesicle to fuse with the presynaptic membrane and release the neurotransmitter into the synapse, a process known as Exocytosis. When the nerve terminal is depolarized and Ca2+ enters, the synapsins become phosphorylated (activated) by the kinase and are thus released from the vesicles, a step that is thought to mobilize the rest of the vesicles for another round of transmitter release. During exocytosis, additional critical protein known as SNAREs is involved to facilitate the process. 4) Involvement of SNAREs during Exocytosis process SNAREs are universally involved in membrane fusion, from yeast to humans. They mediate synaptic vesicle trafficking, which is important for regulating exocytosis. SNARE comes in two forms: Vesicle SNAREs (v-SNARE) reside in the vesicle membranes; Target-membrane SNAREs (t-SNARE) are present in target membranes, such as the plasma membrane. Each synaptic vesicle contains a single type of v-SNARE called synaptobrevin. By contrast, the presynaptic active zone contains two types of t-SNARE proteins: Syntaxin and SNAP-25. During exocytosis the synaptobrevin, on the synaptic vesicle, forms a tight complex with the SNAP-25, and syntaxin, on the plasma membrane. This tight complex of synaptobrevin, syntaxin, and SNAP-25 is known as SNARE complex. SNARE Complex

Figure 2 SNAREs Complex during process of fusion http://www.nature.com/nrm/journal/v3/n7/images/nrm855-f4.gif

5) Recycling synaptic vesicle after exocytosis After fusion, the SNARE complex must be disassembled for efficient vesicle recycling to occur. A cytoplasmic ATPase called NSF binds to SNARE complexes via an adaptor protein called SNAP. NSF and SNAP use the energy of ATP hydrolysis to dissociate SNARE complexes, thereby regenerating free vesicles. After discharging their contents, empty synaptic vesicles are recycled, repeating this cycle to release more transmitters.

Figure 3 SNAP and NSF complex snipping SNARE complex after process of exocytosis http://www.nature.com/nrm/journal/v2/n2/images/nrm0201_098a_f4.gif

Postsynaptic Receptors: Ionotropic and Metabotropic Receptors All receptors for chemical transmitters have region exposed to the external environment of the cell that recognizes and binds the transmitter from the presynaptic cell. Chemical molecules produced from the presynaptic neuron diffuse across the synapse and bind to the receptors on the postsynaptic cell membrane. The binding of neurotransmitter activates the receptors and triggers the ion channels of the postsynaptic neurons to open or close, thereby changing the membrane conductance and membrane potential of the postsynaptic cell. 1) Ionotropic Receptors (Direct Receptors) Neurotransmitters control the opening of ion channels in the postsynaptic cell either directly or indirectly. Receptors that gate ion channels directly, referred to as ionotropic, undergoes a conformational change that opens the channel. Due to their relatively fast synaptic actions, ionotropic receptors are found at synapses in neural circuits that mediate rapid behaviors, such as the stretch receptor reflex.

2) Metobotropic Receptors (Indirect Receptors) On the other hand, receptors that gate ion channels indirectly act by altering intracellular metabolic reactions, referred to as metabotropic receptors. Activation of these receptors often stimulates the production of second messengers, which activate protein kinases. The protein kinases directly phosphorylate (activates) ion channels, leading to their opening or closing. Due to its slower synaptic actions, the metabotropic receptors are known for reinforcing pathways in the process of learning. These slower actions can modulate behavior by altering the excitability of neurons and the strength of the synaptic connections of the neural circuitry mediating behavior.

Figure 4 Ionotropic Receptor vs. Metabotropic Receptor http://webvision.med.utah.edu/imageswv/GLU5.jpeg

Summary Chemical synaptic transmission can be divided into two steps: a transmitting step, in which the presynaptic cell releases a chemical messenger, and a receptive step, in which the transmitter binds to and activates the receptor molecules in the postsynaptic cell. Synaptic vesicles go through fives steps of process before they release a chemical messenger: Trafficking, Ducking, Fusion, Exocytosis, and Recycle. After transmission, neurotransmitters diffuse and bind to receptors in the postsynaptic cell. Neurotransmitters control the opening of ion channels in the postsynaptic cell either directly or indirectly. The activation of receptors changes the membrane conductance and membrane potential of the postsynaptic cell. Thus, the chemical properties of the transmitter do not control the action of transmitter, instead it heavily depends on the properties of the postsynaptic receptors that recognize and bind the transmitter.

Glossary ATPase: A class of enzymes that catalyze the breakdown of ATP in to ADP and a free phosphate ion. This dephosphorylation reaction releases energy, which drives other chemical reactions. Chemical Neurotransmitter: Chemical substance that binds receptors in the postsynaptic membrane of the target cell. Exocytosis: Releasing process of neurotransmitters from the synaptic terminal. NSF: (Also known as N-ethylmaleimide-Sensitive Factor) An ATPase involved in dissociation SNARE complexes once membrane fusion has occurred. Presynaptic Terminal: The distal terminations of axons, which are specialized for the release of neurotransmitters. SNAP: An adaptor protein that assists NSF in dissociating SNARE complexes. SNAREs: an acronym of Soluble NSF Attachment Receptor. The role of SNARE is to mediate vesicle fusion with the presynaptic terminal cell membrane for the exocytosis. SNAREs can be divided into two categories: vesicle (v-SNAREs) and target (t-SNAREs). Synapsins: Protein that is involved in the regulation of neurotransmitter release at synapses. Specifically involved in regulating the number of synaptic vesicles available for exocytosis. Synaptic Vesicle: Lipid molecules that contain molecules of neurotransmitters.

Reference
Kandel, Schwartz and Jessel, Principles of Neural Science, 5th Ed. McGraw-Hill ISBN 978-0-07139001-8, 2013