Synapse

Synapse-

Definition, Structure, Types, Mechanism of Impulse Transmission, Properties & Clinical application

Definition

The synapse is the specialized junction between cells that is used for cell-cell signaling. It is the intercellular junction through which signals are transmitted.

Historically, the term "synapse" was coined by Charles Sherrington in the late nineteenth century. The term implies "contiguity, not continuity" between cells.

A synapse is composed of three main parts:

1. The presynaptic terminal (or synaptic bouton).

2. The postsynaptic membrane (on the target cell).

3. The synaptic cleft (the space between the two membranes).

The average neuron receives many more than 1,000 synaptic inputs; for example, a cerebellar Purkinje neuron may receive as many as 200,000. The human nervous system contains on the order of 100 trillion ($10^{14}$) synapses.

Types of Synapses

Synaptic transmission can be classified into two major types: Electrical and Chemical.

A. Electrical Synapses

• Structure and Function: Electrical synapses are designed for rapid, synchronous transmission. They allow current to flow directly from one neuron to another.

• Gap Junctions: At these synapses, the presynaptic and postsynaptic membranes are separated by a very narrow gap, only 3 to 4 nm wide. The neurons are connected by gap junction channels.

• Connexons: Each gap junction channel consists of two hemichannels called connexons, which are annular assemblies of six connexin peptide subunits. These channels connect the cytoplasm of the two cells, allowing passage of ions, nutrients, metabolites, and other small molecules ($\sim$1000 daltons).

• Speed and Direction: Electrical transmission occurs with a negligible synaptic delay (nearly instantaneous). Most electrical synapses are bidirectional (signals can be transmitted from either cell to the other).

• Physiological Role: They play a role in neuronal synchronization (e.g., coordinating spiking in the thalamic reticular nucleus or helping synchronize circadian rhythm in the suprachiasmatic nucleus).

B. Chemical Synapses

• Prevalence: Most synapses in the mammalian nervous system are chemical synapses.

• Cleft and Structures: The two cells are separated by a synaptic cleft 20 to 40 nm wide (up to 50 nm at the neuromuscular junction). The presynaptic terminal contains numerous small ($\sim$40 nm diameter) synaptic vesicles (SVs) filled with high concentrations of neurotransmitters, concentrated near the specialized region called the active zone.

• Directionality: Chemical synapses are unidirectional (polarized), propagating current only from the presynaptic cell (releasing transmitter) to the postsynaptic cell (containing receptors).

• Function: They afford specificity, variety, and fine tuning of neurotransmission, largely determined by the more than 100 different neurotransmitter molecules and their specific receptors.

• Wiring Transmission: This type of transmission is sometimes referred to as "wiring transmission" because it relies on the direct, structured connection between presynaptic and postsynaptic elements.

Mechanism of Impulse Transmission (Chemical Synapse)

Synaptic transmission at a chemical synapse involves a precisely choreographed process summarized in seven key steps:

1. Neurotransmitter Synthesis and Storage: Neurotransmitter molecules (e.g., Acetylcholine, ACh) are synthesized (e.g., by choline acetyltransferase, forming ACh from acetyl CoA and choline) and packaged into synaptic vesicles (SVs). The packaging process is often driven by secondary active transporters coupling the uphill uptake of the neurotransmitter to the downhill movement of H+, which is maintained by a V type ATPase. The SVs then dock at the active zone.
   
   

2. Action Potential (AP) Arrival: An AP, propagated along the axon, arrives at the presynaptic nerve terminal, causing depolarization.
   
   

3. Ca++ Influx: The depolarization opens voltage-gated Ca++ channels located in the plasma membrane of the terminal bouton. This results in Ca++ influx.
   
   

4. Exocytosis (Neurotransmitter Release): The increase in intracellular Ca++ concentration, Ca++ acts as a signal to trigger the fusion of docked SVs with the presynaptic membrane.
   
   

   • This fusion is mediated by a complex of SNARE proteins (Synaptobrevin, Syntaxin, and SNAP-25) that bring the vesicle and plasma membranes close together.

   • The Ca++ sensor protein Synaptotagmin binds Ca++ and interacts with the SNARE complex, triggering the formation of a fusion pore and the subsequent release of neurotransmitter molecules into the synaptic cleft.

   • Neurotransmitter is released in quantal packets (the content of a single SV).

5. Receptor Binding and Activation: The neurotransmitter diffuses across the synaptic cleft and binds to specific receptor proteins (integral membrane proteins) located in the postsynaptic membrane.
   
   

   • Binding activates the receptor, which can be either ionotropic (ligand-gated ion channels, causing direct change in membrane conductance) or metabotropic (G protein–coupled receptors, initiating an intracellular signaling cascade).

6. Postsynaptic Response: Activation of the receptor leads to a change in the membrane potential of the postsynaptic cell:
   
   

   • Excitatory Postsynaptic Potential (EPSP): Increases the probability of the postsynaptic cell firing an AP (e.g., glutamate activating AMPARs/NMDARs, ACh activating nicotinic AChRs).

   • Inhibitory Postsynaptic Potential (IPSP): Decreases the probability of the postsynaptic cell firing an AP (e.g., GABA or Glycine activating Cl- selective channels).

7. Termination: Neurotransmission is terminated by removal of the transmitter from the synaptic cleft, primarily via three mechanisms:
   
   

   • Diffusion: Transmitter molecules diffuse away from the synapse (a clearance mechanism effective on the order of a millisecond or so).

   • Enzymatic Deactivation: Destruction of the transmitter (e.g., ACh is rapidly hydrolyzed by Acetylcholinesterase, AChE).

   • Reuptake: Na+ dependent transport systems take up the transmitter (e.g., monoamines) into the presynaptic nerve terminal or adjacent glial cells.

Properties of Synapses

I. Integration and Summation

The neuronal cell body and dendrite membranes integrate synaptic inputs over both space and time. CNS neurons continuously sum their excitatory (EPSP) and inhibitory (IPSP) inputs; the resulting net depolarization at the axon hillock determines whether an AP is fired.

• Spatial Summation: Occurs when two or more excitatory inputs from different presynaptic axons converge and arrive simultaneously at the postsynaptic neuron. The individual depolarizations sum to produce a larger response. This process is affected by the length constant (lambda) of the neuron; a larger lambda means inputs from distant synapses can sum effectively.

• Temporal Summation: Occurs when two excitatory inputs from a single presynaptic axon arrive in rapid succession. The consecutive postsynaptic depolarizations overlap in time and add stepwise. This is affected by the membrane time constant (tm); a larger tm means the synaptic response lasts longer and can sum with a later input.

II. Synaptic Plasticity

Synaptic plasticity refers to activity-dependent changes in the effectiveness (strength) of synapses.

Synaptic Delay

The time required for signal transmission across a chemical synapse (approx. 2.5 msec, e.g., in a squid giant synapse). Electrical synapses have a negligible delay.

Time taken for transmitter release, diffusion, and receptor activation.

Synaptic Facilitation (Short-Term)

The second response (I-2) is larger than the first (I-1) when stimuli are delivered at short intervals.

Thought to be caused by residual Ca++ remaining in the presynaptic terminal after the first AP.

Synaptic Depression (Short-Term)

The second response (I-2) is depressed relative to the first.

This results from the depletion of the readily releasable pool of synaptic vesicles at the active zone.

Post-Tetanic Potentiation (PTP) (Short-Term)

A transient, sharp augmentation of response immediately following high-frequency (tetanic) stimulation, lasting tens of seconds.

Persists significantly longer than the presynaptic Ca++ signal and may involve Ca++ activated protein kinase (PKC).

Long-Term Potentiation (LTP)

A long-lasting enhancement of synaptic efficacy induced by high-frequency stimulation (HFS).

Involves NMDAR activation leading to Ca++ influx, subsequent activation of protein kinase CaMKII, and the insertion of additional AMPA receptors into the postsynaptic density. Critical for memory consolidation.

Long-Term Depression (LTD)

A long-lasting attenuation of synaptic efficacy induced by prolonged low-frequency stimulation (LFS).

Ca++ influx through NMDARs activates phosphatases (Calcineurin/PP1) that enable the removal of AMPA receptors from the postsynaptic membrane.

Clinical Application of the Various Disorders of Synapse

Synaptic dysfunction underlies numerous clinical conditions, ranging from neurodegenerative diseases to specific paralytic syndromes.

I. Disorders Affecting Neurotransmitter Release

• Botulinum Toxin (BoTox): 

These toxins A, E, C1 act as endoproteinases that block synaptic vesicle fusion and neurotransmitter release. They specifically cleave SNARE proteins (BoTox A and E cleave SNAP-25; BoTox C1 cleaves syntaxin) necessary for the core complex formation.

• Tetanus Toxin: 

This toxin acts as an endoproteinase that digests Synaptobrevin (a v-SNARE), resulting in potent inhibition of synaptic vesicle exocytosis.

• a-Latrotoxin (a-LTX): 

From the black widow spider, it induces massive, uncontrolled release and depletion of synaptic vesicles by creating Ca++ permeable channels in the presynaptic membrane.

• Lambert-Eaton Syndrome: 

Associated with IgG antibodies that block voltage-dependent Ca++ channels in the presynaptic terminal, leading to impaired transmitter release.

II. Disorders Affecting the Neuromuscular Junction (NMJ)

The NMJ is a well-studied chemical synapse, and numerous diseases involve defects here.

• Myasthenia Gravis: 

An autoimmune disease involving defective neurotransmission at the NMJ.

• Nicotinic ACh Receptor (nAChR) Defects:

Disorders can result from defects in the nAChR channel structure, such as Congenital Myasthenic Syndrome caused by mutations leading to prolonged AChR channel openings.

• Pharmacological Intervention: 

Drugs like curare are used to block nAChRs and reduce synaptic amplitude.

III. Central Nervous System (CNS) Disorders

• Excitotoxicity: 

Occurs when excessive glutamate activates NMDA receptors, causing excessive Ca++ entry into neurons, leading to cell death. This process is responsible for neuron death in ischemic strokes (due to impaired glutamate uptake from the synapse) and is believed to contribute to neurodegenerative diseases like Parkinson’s disease, Alzheimer’s, and Multiple Sclerosis.

• Parkinson’s Disease: 

This is a neurodegenerative disorder characterized by the degeneration of dopaminergic axons originating from the substantia nigra. Treatment often involves administering levodopa (L-dopa), a precursor molecule that can cross the blood-brain barrier, unlike dopamine itself.

• Affective Disorders (e.g., Depression):

Therapeutic agents, such as Selective Serotonin Reuptake Inhibitors (SSRIs), work by interfering with the reuptake mechanisms of monoamine neurotransmitters (like serotonin) to modulate their concentration in the synapse.

• Startle Disease: 

Mutations in the glycine receptor (GlyR) are linked to Human Startle Disease; GlyRs are Cl-selective channels mediating inhibitory synaptic transmission. The inhibitory effect of glycine can be blocked by strychnine.