Medical School · Year 1 · Physiology · includes a quiz and discussion video

Lecture 3: Synaptic Transmission

Unit 1.6: Physiology Foundations

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the structure and function of chemical and electrical synapses
2. Explain the steps of neurotransmitter release and the role of calcium
3. Describe postsynaptic potentials and synaptic integration
4. Identify major neurotransmitters and their receptors
5. Explain mechanisms of synaptic plasticity
6. Apply synaptic physiology to pharmacological interventions

Overview of Synapses

Synapses are specialized junctions that enable signal transmission between neurons and between neurons and their target cells, including muscle fibers and gland cells. This intercellular communication forms the basis for all nervous system function, from simple reflexes to complex cognitive processes.

Two fundamental types of synapses exist: chemical and electrical. Chemical synapses transmit signals by releasing neurotransmitter molecules that diffuse across a narrow cleft to bind receptors on the target cell. This mechanism introduces a synaptic delay of 0.5-5 milliseconds but offers tremendous flexibility through diverse neurotransmitters, receptor types, and regulatory mechanisms. The plasticity of chemical synapses—their ability to strengthen or weaken over time—underlies learning and memory.

Electrical synapses transmit signals through gap junctions, specialized channels that directly connect the cytoplasm of adjacent cells. Ions and small molecules flow through these channels, allowing essentially instantaneous transmission without synaptic delay. Electrical synapses provide rapid, reliable communication but lack the modulatory capacity of chemical synapses. They appear in circuits requiring precise synchronization, such as cardiac conduction pathways and certain brain regions coordinating rhythmic activity.

Synaptic arrangements describe the anatomical relationships between presynaptic and postsynaptic elements. Axodendritic synapses, connecting axon terminals to dendrites, represent the most common arrangement for integrative processing. Axosomatic synapses on cell bodies exert powerful effects due to their proximity to the axon hillock. Axoaxonic synapses between axon terminals modulate neurotransmitter release through presynaptic inhibition or facilitation. Dendrodendritic synapses between dendrites enable local processing within neural circuits.

<image>Panel A: Chemical synapse cross-section showing presynaptic terminal with vesicles, synaptic cleft, and postsynaptic membrane with receptors. Panel B: Electrical synapse with gap junction channels formed by connexon proteins directly connecting adjacent cells. Panel C: Synaptic arrangements on a neuron including axodendritic, axosomatic, and axoaxonic synapses. Panel D: Comparison of chemical versus electrical synapse properties including delay, directionality, and plasticity.</image>

Chemical Synapse Structure

The presynaptic terminal (bouton) contains the molecular machinery for neurotransmitter storage and release. Synaptic vesicles, small membrane-bound spheres approximately 40 nanometers in diameter, store neurotransmitter at concentrations far exceeding cytoplasmic levels. These vesicles cluster at active zones, specialized membrane regions positioned directly across from postsynaptic receptors. Mitochondria concentrate in presynaptic terminals, reflecting the high energy demands of neurotransmitter synthesis, vesicle recycling, and ionic gradient maintenance. Voltage-gated calcium channels localize to active zones, positioned to trigger vesicle fusion when opened by arriving action potentials.

The synaptic cleft separating presynaptic and postsynaptic membranes spans approximately 20-40 nanometers, much wider than the gap at electrical synapses. This space contains extracellular matrix proteins that help maintain synaptic structure and may influence neurotransmitter diffusion. Enzymes such as acetylcholinesterase at cholinergic synapses localize to the cleft, enabling rapid signal termination.

The postsynaptic membrane contains the receptors that bind neurotransmitter and generate the postsynaptic response. These receptors cluster at synapses through interactions with scaffolding proteins that form the postsynaptic density, a protein-rich specialization visible in electron microscopy. Receptor density and subtype composition vary between synapses and can change with activity, providing a mechanism for synaptic modification. Associated ion channels, enzymes, and signaling molecules complete the postsynaptic apparatus.

<image>Panel A: Presynaptic terminal ultrastructure showing active zone with docked vesicles and reserve pool vesicles for neurotransmitter storage. Panel B: Voltage-gated calcium channels positioned at the active zone with mitochondria providing ATP nearby. Panel C: Synaptic cleft structure containing extracellular matrix proteins between pre- and postsynaptic membranes. Panel D: Postsynaptic membrane with clustered ionotropic and metabotropic receptors and the electron-dense postsynaptic density region.</image>

Steps of Chemical Synaptic Transmission

The sequence of events at a chemical synapse transforms the electrical signal of an action potential into chemical transmission across the cleft, then back to an electrical signal in the postsynaptic cell. Each step offers opportunities for modulation and represents potential targets for pharmacological intervention.

Arrival of an action potential at the presynaptic terminal depolarizes the membrane, opening voltage-gated calcium channels concentrated at active zones. Unlike sodium channels, these calcium channels (primarily P/Q-type and N-type) remain open longer and do not inactivate rapidly, allowing substantial calcium entry during the action potential. The resulting rise in intracellular calcium concentration, from resting levels of approximately 100 nanomolar to peak levels exceeding 10 micromolar near the channel, triggers vesicle fusion.

Calcium triggers vesicle fusion through interaction with synaptotagmin, a calcium sensor protein anchored in the vesicle membrane. Calcium binding to synaptotagmin's C2 domains produces conformational changes that accelerate the fusion process mediated by SNARE proteins. The SNARE complex consists of synaptobrevin (also called VAMP) on the vesicle membrane and syntaxin and SNAP-25 on the presynaptic membrane. These proteins zip together to bring vesicle and membrane into close apposition, overcoming the energy barrier to membrane fusion.

Upon fusion, the vesicle contents release into the synaptic cleft through exocytosis. Neurotransmitter diffuses across the cleft in microseconds, reaching postsynaptic receptors that recognize and bind specific transmitter molecules. Receptor activation produces the postsynaptic response, either through direct channel opening (ionotropic receptors) or through G-protein signaling cascades (metabotropic receptors).

Neurotransmitter release occurs in discrete packets (quanta), with each quantum corresponding to the contents of a single vesicle. At the neuromuscular junction, spontaneous release of single vesicles produces miniature end-plate potentials (MEPPs), small depolarizations of consistent size that provided early evidence for vesicular release.

<image>Panel A: Action potential arrival at the presynaptic terminal triggering calcium channel opening and calcium influx. Panel B: Calcium binding to synaptotagmin and SNARE complex assembly bringing vesicle and membrane together for fusion. Panel C: Vesicle fusion and neurotransmitter release into the synaptic cleft with diffusion to postsynaptic membrane. Panel D: Postsynaptic receptor activation opening ion channels to produce depolarizing or hyperpolarizing responses.</image>

Signal Termination

Termination of synaptic transmission is essential for temporal precision and for preventing receptor desensitization or excitotoxicity from prolonged neurotransmitter exposure. Three mechanisms accomplish signal termination: reuptake, enzymatic degradation, and diffusion.

Reuptake represents the primary termination mechanism for monoamine neurotransmitters and amino acid transmitters. Transporter proteins in the presynaptic membrane and surrounding glial cells actively transport neurotransmitter from the cleft back into the cytoplasm, where it can be repackaged into vesicles for subsequent release. The serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET) are critical therapeutic targets; selective serotonin reuptake inhibitors (SSRIs) block SERT to increase serotonergic transmission, while cocaine blocks DAT to enhance dopaminergic effects underlying its addiction potential. GABA transporters (GAT) and glutamate transporters (EAAT) clear inhibitory and excitatory amino acid transmitters, respectively.

Enzymatic degradation within the synaptic cleft provides rapid termination at cholinergic synapses. Acetylcholinesterase, anchored in the synaptic basal lamina, hydrolyzes acetylcholine into acetate and choline within milliseconds of release. The choline is then taken up by the presynaptic terminal for resynthesis of acetylcholine. Catecholamines undergo enzymatic degradation by monoamine oxidase (MAO) in mitochondria and catechol-O-methyltransferase (COMT) in the cytoplasm and extracellular space, though reuptake typically occurs before degradation.

Diffusion carries neurotransmitter away from the synapse and represents a universal termination mechanism. While slower than reuptake or enzymatic degradation, diffusion becomes significant for transmitters released extrasynaptically or for synapses lacking efficient reuptake mechanisms. The dilution of neurotransmitter concentration reduces receptor occupancy and allows signal termination.

<image>Panel A: Reuptake mechanism showing transporter proteins pumping neurotransmitter back into the presynaptic terminal for vesicular repackaging. Panel B: Enzymatic degradation at cholinergic synapses with acetylcholinesterase cleaving acetylcholine into acetate and choline. Panel C: Diffusion mechanism showing neurotransmitter spreading away from the synapse down its concentration gradient. Panel D: Summary table of predominant termination mechanisms for major neurotransmitters including monoamines and acetylcholine.</image>

Postsynaptic Potentials

Excitatory postsynaptic potentials (EPSPs) depolarize the postsynaptic membrane, bringing it closer to the threshold for action potential generation. EPSPs result from opening of channels permeable to cations, typically sodium and potassium. The driving force for sodium entry exceeds that for potassium exit at resting potential, producing net positive charge entry and depolarization. Glutamate acting at AMPA and NMDA receptors generates EPSPs at most excitatory synapses in the central nervous system, while acetylcholine at nicotinic receptors generates EPSPs at the neuromuscular junction and other peripheral synapses.

Inhibitory postsynaptic potentials (IPSPs) hyperpolarize the postsynaptic membrane, moving it away from threshold and reducing the probability of action potential generation. IPSPs result from opening of chloride channels or potassium channels. At typical chloride equilibrium potentials (near or slightly more negative than resting potential), GABA binding to GABA-A receptors opens chloride channels that either hyperpolarize the membrane or stabilize it against depolarization. Glycine produces similar inhibitory effects at its ionotropic receptor in the spinal cord and brainstem.

Postsynaptic potentials differ fundamentally from action potentials in their properties. PSPs are graded, with amplitude proportional to the amount of neurotransmitter released and receptors activated. They decay with distance from the synapse because they spread passively through the cytoplasm without regeneration. They can summate when multiple inputs occur together in space or time. These properties allow PSPs to integrate multiple inputs, determining whether the neuron will fire.

<image>Panel A: Excitatory postsynaptic potential showing membrane depolarization toward threshold from sodium and cation influx. Panel B: Inhibitory postsynaptic potential showing membrane hyperpolarization away from threshold from chloride influx or potassium efflux. Panel C: Comparison overlay of EPSP and IPSP demonstrating opposite effects relative to threshold and resting potential. Panel D: Ionic mechanisms underlying each postsynaptic potential type with channel opening and ion flow patterns.</image>

Synaptic Integration

Spatial summation occurs when multiple synaptic inputs at different locations on a neuron combine their effects. EPSPs from multiple active synapses sum algebraically, and if their combined amplitude reaches threshold at the axon hillock, an action potential results. Similarly, IPSPs subtract from EPSPs, reducing the probability of reaching threshold. The effectiveness of a synapse in influencing action potential generation depends on its distance from the axon hillock; proximal synapses have greater influence because their PSPs decay less before reaching the integration site.

Temporal summation occurs when a single synapse activates repeatedly in rapid succession, before the previous PSP has decayed completely. If a second EPSP arrives during the falling phase of the first, the membrane potential rises higher than either EPSP alone would achieve. Continued rapid stimulation can summate multiple EPSPs to reach threshold. The time constant of the membrane determines how rapidly PSPs decay and therefore how close in time successive inputs must occur to summate effectively.

The axon hillock serves as the integration site where the decision to fire is made. This region contains the highest density of voltage-gated sodium channels, giving it the lowest threshold for action potential initiation. All synaptic inputs throughout the dendritic tree and cell body spread to the axon hillock, where their summated effect determines the membrane potential. When this potential reaches threshold, an action potential initiates at the axon hillock and propagates along the axon.

A typical neuron receives thousands of synaptic inputs, both excitatory and inhibitory. The balance of these inputs at any moment determines the neuron's output. This integrative capacity allows individual neurons to perform complex computational operations that underlie information processing in the nervous system.

<image>Panel A: Neuron receiving multiple excitatory and inhibitory synaptic inputs across the dendritic tree and cell body. Panel B: Spatial summation showing simultaneous EPSPs from different locations combining to reach threshold. Panel C: Temporal summation showing rapid sequential EPSPs from one synapse building to reach threshold. Panel D: Axon hillock integration zone with high sodium channel density as the site of action potential initiation.</image>

Receptor Types

Ionotropic receptors (ligand-gated ion channels) combine receptor and channel functions in a single protein complex. When neurotransmitter binds to the extracellular domain, the channel pore opens within milliseconds, allowing specific ions to flow according to their electrochemical gradients. This direct coupling produces fast synaptic responses lasting only as long as neurotransmitter remains bound. Nicotinic acetylcholine receptors at the neuromuscular junction exemplify ionotropic receptors, opening cation channels that depolarize muscle fibers within milliseconds of acetylcholine release. GABA-A receptors open chloride channels, producing the rapid inhibitory responses essential for circuit function. AMPA receptors mediate fast glutamatergic transmission, while NMDA receptors add complexity by requiring both glutamate binding and membrane depolarization to relieve their magnesium block.

Metabotropic receptors (G-protein coupled receptors) produce slower, longer-lasting, and more diverse effects through intracellular signaling cascades. These seven-transmembrane proteins couple to heterotrimeric G proteins that dissociate upon receptor activation. G protein subunits then modulate effector enzymes (adenylyl cyclase, phospholipase C) or ion channels. Second messengers including cyclic AMP, inositol trisphosphate, and diacylglycerol amplify the signal and activate protein kinases that phosphorylate diverse cellular targets. Muscarinic acetylcholine receptors, adrenergic receptors, dopamine receptors, and metabotropic glutamate receptors all belong to this family. Response latencies of seconds to minutes and durations of minutes to hours contrast with the millisecond timescale of ionotropic signaling.

The two receptor types serve complementary functions. Ionotropic receptors provide the speed necessary for rapid information transfer, reflex responses, and temporal precision. Metabotropic receptors modulate neuronal excitability, regulate synaptic strength, and produce the sustained changes underlying hormonal effects, mood regulation, and memory consolidation.

<image>Panel A: Ionotropic receptor structure showing pentameric ligand-gated channel with neurotransmitter binding sites and central ion pore. Panel B: Fast ionotropic receptor kinetics with millisecond activation and examples including nicotinic and GABA-A receptors. Panel C: Metabotropic receptor structure showing seven-transmembrane protein coupled to G protein signaling cascades. Panel D: Slow metabotropic receptor effects lasting seconds to minutes through second messenger pathways including cAMP and IP3.</image>

Major Neurotransmitters

Acetylcholine, the first neurotransmitter discovered, serves critical roles at the neuromuscular junction, in the autonomic nervous system, and in central circuits involved in attention, learning, and memory. Synthesis from choline and acetyl-CoA requires choline acetyltransferase. Two receptor families mediate acetylcholine effects: nicotinic receptors (ionotropic, excitatory) at the neuromuscular junction and autonomic ganglia, and muscarinic receptors (metabotropic) in smooth muscle, cardiac muscle, and CNS. Acetylcholinesterase rapidly terminates transmission by hydrolyzing acetylcholine.

Glutamate functions as the primary excitatory neurotransmitter in the central nervous system, present at the majority of CNS synapses. Three ionotropic receptor types (AMPA, NMDA, and kainate) and eight metabotropic receptor types mediate its effects. NMDA receptors play special roles in synaptic plasticity due to their calcium permeability and voltage-dependent magnesium block that requires coincident pre- and postsynaptic activity. Excessive glutamate causes excitotoxicity through calcium overload, contributing to neuronal death in stroke and neurodegeneration.

GABA (gamma-aminobutyric acid) serves as the primary inhibitory neurotransmitter in the brain, with glycine filling this role in the spinal cord and brainstem. GABA-A receptors are ionotropic chloride channels enhanced by benzodiazepines, barbiturates, and alcohol. GABA-B receptors are metabotropic, coupling to potassium channels to produce slow inhibition. The balance between glutamatergic excitation and GABAergic inhibition maintains appropriate circuit activity; imbalance underlies epilepsy.

The catecholamines—dopamine, norepinephrine, and epinephrine—share a synthetic pathway beginning with tyrosine. Dopamine signals through D1-D5 receptors to regulate reward, motivation, and movement; its deficiency produces Parkinson's disease while excessive signaling contributes to schizophrenia. Norepinephrine acting at alpha and beta adrenergic receptors modulates arousal, attention, and stress responses. Serotonin (5-hydroxytryptamine) signals through at least 14 receptor subtypes to influence mood, sleep, appetite, and pain, making it a major target for antidepressant medications.

<image>Panel A: Cholinergic and dopaminergic projection systems showing pathways from basal forebrain, substantia nigra, and ventral tegmental area. Panel B: Noradrenergic projections from locus coeruleus and serotonergic projections from raphe nuclei throughout the brain. Panel C: Neurotransmitter synthesis pathways and receptor types for each major system. Panel D: GABAergic and glutamatergic local circuits distributed throughout the cortex with their key functions.</image>

Synaptic Plasticity

Short-term plasticity modifies synaptic strength over timescales of milliseconds to minutes and reflects changes in presynaptic neurotransmitter release. Facilitation occurs when residual calcium from a preceding action potential adds to calcium entry from subsequent action potentials, enhancing vesicle fusion probability. Paired-pulse facilitation, where the second of two closely spaced stimuli produces a larger response, exemplifies this mechanism. Synaptic depression occurs when vesicle depletion reduces the readily releasable pool, decreasing transmitter release with sustained activity. Post-tetanic potentiation, lasting minutes after high-frequency stimulation, results from enhanced calcium mobilization and vesicle priming.

Long-term potentiation (LTP) produces persistent strengthening of synaptic connections lasting hours to years, representing a leading cellular model for learning and memory. LTP at hippocampal synapses requires strong, high-frequency stimulation that produces sufficient postsynaptic depolarization to relieve the magnesium block of NMDA receptors. With NMDA receptors unblocked, glutamate binding opens the channel, allowing calcium entry that triggers signaling cascades including calcium/calmodulin-dependent protein kinase II (CaMKII) activation. This leads to phosphorylation and increased trafficking of AMPA receptors to the postsynaptic membrane, increasing the response to subsequent glutamate release. The NMDA receptor functions as a coincidence detector, requiring simultaneous presynaptic activity (glutamate release) and postsynaptic activity (depolarization), implementing the Hebbian principle that neurons that fire together wire together.

Long-term depression (LTD) produces persistent weakening of synaptic connections and may be equally important for learning by allowing selective strengthening of relevant connections while weakening others. LTD typically results from low-frequency stimulation or modest calcium entry that activates phosphatases rather than kinases, leading to AMPA receptor internalization. This bidirectional plasticity allows synaptic weights to adjust according to patterns of activity.

<image>Panel A: Short-term facilitation showing enhanced second EPSP from residual calcium and short-term depression from vesicle depletion. Panel B: LTP induction with high-frequency stimulation relieving NMDA receptor magnesium block allowing calcium entry. Panel C: Calcium-dependent signaling cascade activating CaMKII leading to AMPA receptor insertion. Panel D: Potentiated state with sustained larger EPSP amplitude and increased postsynaptic receptor density.</image>

Clinical Applications

Myasthenia gravis exemplifies autoimmune disruption of synaptic transmission. Autoantibodies target nicotinic acetylcholine receptors at the neuromuscular junction, reducing receptor density and impairing transmission. Patients develop fatigable weakness affecting ocular, bulbar, and limb muscles. Diagnosis relies on antibody detection, decremental response on repetitive nerve stimulation, and improvement with acetylcholinesterase inhibitors such as pyridostigmine, which prolong acetylcholine presence in the cleft and partially compensate for reduced receptor number. Immunosuppression and thymectomy address the underlying autoimmune process.

Parkinson's disease results from degeneration of dopaminergic neurons in the substantia nigra pars compacta, reducing dopamine release in the striatum. The resulting dopamine deficiency produces the cardinal motor features: bradykinesia, rigidity, resting tremor, and postural instability. Treatment aims to restore dopaminergic transmission through levodopa (the dopamine precursor that crosses the blood-brain barrier), dopamine agonists, or inhibitors of dopamine-degrading enzymes (MAO-B inhibitors, COMT inhibitors).

Epilepsy reflects excessive, synchronized neuronal activity that may result from reduced GABAergic inhibition or enhanced glutamatergic excitation. Anticonvulsant medications target these imbalances: benzodiazepines enhance GABA-A receptor function, while other agents block sodium channels or modulate glutamate signaling.

Depression has been linked to monoamine neurotransmitter deficiency, though the full picture is more complex. Antidepressants that enhance serotonergic, noradrenergic, or dopaminergic transmission provide clinical benefit, including SSRIs (blocking serotonin reuptake), SNRIs (blocking serotonin and norepinephrine reuptake), and MAO inhibitors (preventing monoamine degradation).

Botulinum toxin disrupts synaptic transmission by cleaving SNARE proteins, preventing vesicle fusion and acetylcholine release at neuromuscular junctions. This mechanism produces flaccid paralysis, but controlled local injection provides therapeutic benefit in dystonia, spasticity, and cosmetic applications. Tetanus toxin similarly cleaves SNAREs but selectively affects inhibitory interneurons, disinhibiting motor neurons and producing the characteristic spastic paralysis.

<image>Panel A: Myasthenia gravis showing antibodies bound to acetylcholine receptors reducing receptor density with decremental EMG response. Panel B: Parkinson's disease with degenerated dopaminergic neurons from substantia nigra and levodopa therapeutic approach. Panel C: Epilepsy mechanisms showing imbalance between GABAergic inhibition and glutamatergic excitation with benzodiazepine targets. Panel D: Botulinum toxin mechanism cleaving SNARE proteins to prevent vesicle fusion and neurotransmitter release.</image>

Summary

Chemical synapses transmit signals via neurotransmitter release, while electrical synapses provide rapid transmission through gap junctions. Neurotransmitter release requires action potential-triggered calcium influx and SNARE-mediated vesicle fusion with the presynaptic membrane. Signal termination occurs through reuptake transporters (monoamines, amino acids), enzymatic degradation (acetylcholine), and diffusion.

Excitatory postsynaptic potentials result from cation influx and bring the membrane toward threshold, while inhibitory postsynaptic potentials result from chloride influx or potassium efflux and move the membrane away from threshold. Synaptic integration at the axon hillock sums spatial inputs from multiple synapses and temporal inputs from rapid successive activation.

Ionotropic receptors provide fast responses through direct channel opening, while metabotropic receptors produce slower, amplified, and more prolonged effects through G-protein signaling cascades. Major neurotransmitters include acetylcholine, glutamate (excitatory), GABA (inhibitory), and the monoamines (dopamine, norepinephrine, serotonin).

Long-term potentiation and long-term depression modify synaptic strength persistently through NMDA receptor-dependent mechanisms, providing a cellular basis for learning and memory. Many neurological and psychiatric conditions result from synaptic dysfunction, and many therapeutics target synaptic transmission.

Key Terms

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