Synaptic Transmission Steps

Why This Matters

Synaptic transmission is the foundation of everything your brain does—every thought, emotion, memory, and movement depends on neurons successfully passing signals to one another. You're being tested on more than just the sequence of events; you need to understand how electrical signals convert to chemical signals, what triggers neurotransmitter release, and how the postsynaptic neuron integrates information. These concepts appear repeatedly in questions about drug mechanisms, neural plasticity, and psychiatric disorders.

Here's the key insight: drugs work by hijacking specific steps in this process. SSRIs block reuptake. Botox prevents vesicle fusion. Benzodiazepines enhance receptor activity. If you understand where in the transmission sequence each step occurs and why it matters, you'll be able to predict how any drug affects neural communication. Don't just memorize the order—know what molecular mechanism each step demonstrates and where pharmacological intervention can occur.

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Signal Arrival: The Electrical Phase

The transmission process begins with purely electrical events. The action potential serves as the trigger that initiates the cascade—without it reaching the terminal, nothing else happens.

Action Potential Reaches Presynaptic Terminal

• Electrical signal propagation—the action potential travels down the axon via sequential depolarization until it reaches the axon terminal
• All-or-nothing principle applies here; the signal arrives at full strength regardless of distance traveled
• Terminal depolarization is the critical trigger that activates voltage-sensitive proteins embedded in the presynaptic membrane

Voltage-Gated Calcium Channels Open

• Depolarization-sensitive channels respond specifically to the membrane potential change caused by the arriving action potential
• $Ca^{2+}$ channels are distinct from the $Na^+$ channels involved in action potential propagation—this specificity matters for drug targeting
• Electrical-to-chemical conversion begins here; this is the pivotal transition point in synaptic transmission

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Release Machinery: The Secretion Phase

Calcium entry sets off a molecular cascade that physically moves neurotransmitters from storage vesicles into the synaptic cleft. This phase converts the electrical code into a chemical message through exocytosis.

Calcium Influx into Presynaptic Terminal

• Concentration gradient drives entry—extracellular $Ca^{2+}$ is much higher than intracellular, so ions rush in when channels open
• Calcium acts as a second messenger, binding to sensor proteins that trigger the fusion machinery
• Local concentration matters—$Ca^{2+}$ levels spike dramatically near the channels, creating microdomains that activate nearby vesicles

Synaptic Vesicles Fuse with Presynaptic Membrane

• SNARE proteins (v-SNAREs on vesicles, t-SNAREs on target membrane) zipper together to pull membranes into contact
• Synaptotagmin is the calcium sensor that triggers fusion when $Ca^{2+}$ binds to it
• Botulinum toxin cleaves SNARE proteins, which is why it paralyzes muscles—no fusion means no acetylcholine release

Neurotransmitters Released into Synaptic Cleft

• Exocytosis releases the entire contents of fused vesicles into the synaptic cleft simultaneously
• Quantal release—neurotransmitters are released in discrete packets (quanta), not continuously
• Diffusion across the cleft takes only microseconds due to the narrow gap (approximately 20-40 nanometers)

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Reception: The Postsynaptic Response Phase

Once neurotransmitters cross the cleft, the postsynaptic neuron must detect and interpret the chemical signal. Receptor binding translates the chemical message back into electrical changes in the receiving neuron.

Neurotransmitters Bind to Postsynaptic Receptors

• Lock-and-key specificity—each neurotransmitter fits particular receptor subtypes, explaining why dopamine doesn't activate serotonin receptors
• Receptor density and affinity determine signal strength; more receptors or tighter binding means stronger response
• Agonist drugs mimic neurotransmitters at this step, while antagonists block binding without activating receptors

Ion Channels Open or Close on Postsynaptic Membrane

• Ionotropic receptors are ligand-gated channels that open directly when neurotransmitter binds (fast transmission, milliseconds)
• Metabotropic receptors trigger intracellular signaling cascades that indirectly affect channels (slower but longer-lasting effects)
• Ion selectivity determines the effect—$Na^+$ or $Ca^{2+}$ influx excites; $Cl^-$ influx or $K^+$ efflux inhibits

Postsynaptic Potential Generated (EPSP or IPSP)

• EPSPs (excitatory postsynaptic potentials) depolarize the membrane toward threshold, increasing firing probability
• IPSPs (inhibitory postsynaptic potentials) hyperpolarize the membrane away from threshold, decreasing firing probability
• Summation is key—the postsynaptic neuron integrates thousands of EPSPs and IPSPs to determine whether to fire

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Termination: The Reset Phase

Transmission must end for the system to reset and respond to new signals. Without termination mechanisms, neurotransmitters would continuously activate receptors, causing overstimulation or desensitization.

Neurotransmitter Reuptake or Degradation

• Reuptake transporters pump neurotransmitters back into the presynaptic terminal for recycling—SSRIs block serotonin reuptake, cocaine blocks dopamine reuptake
• Enzymatic degradation breaks down neurotransmitters in the cleft; acetylcholinesterase destroys acetylcholine, MAO breaks down monoamines
• Termination method varies by neurotransmitter—acetylcholine relies mainly on degradation, while dopamine and serotonin rely mainly on reuptake

Synaptic Vesicle Recycling

• Endocytosis retrieves vesicle membrane from the presynaptic surface after fusion
• Vesicle refilling requires specific transporters that pack neurotransmitters back into recycled vesicles
• Recycling rate limits sustained transmission—during high-frequency firing, vesicle depletion can cause synaptic fatigue

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Quick Reference Table

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Self-Check Questions

1. Which two steps involve calcium, and what different roles does $Ca^{2+}$ play in each?

2. A drug blocks voltage-gated calcium channels at the presynaptic terminal. Which subsequent steps in transmission would be affected, and why?

3. Compare and contrast how SSRIs and MAO inhibitors both increase monoamine signaling—what step does each target, and how do their mechanisms differ?

4. If a neuron receives simultaneous input producing 5 EPSPs and 3 IPSPs, what determines whether it fires an action potential?

5. Botulinum toxin and curare both cause paralysis, but they target different steps in transmission. Identify which step each affects and explain why both produce similar symptoms despite different mechanisms.