Synaptic Transmission

Spec Mapping — OCR H420 Module 5.1.3 — Neuronal communication, content statements covering the structure and function of cholinergic synapses, including the role of voltage-gated Ca²⁺ channels, vesicle fusion, neurotransmitter release, post-synaptic receptor binding, EPSP / IPSP generation, summation (spatial and temporal), and neurotransmitter removal (refer to the official OCR H420 specification document for exact wording). The synapse is where the nervous system performs its computation: every memory, every decision, every reflex routes through synaptic transmission.

Action potentials cannot cross from one neurone to the next directly. Instead, every nerve impulse arriving at the end of an axon is briefly converted into a chemical signal, crosses a tiny gap, and is converted back into a new electrical signal in the next cell. These microscopic conversion stations are called synapses, and they are where the nervous system does much of its computation.

The chemical nature of synaptic transmission was established by Otto Loewi in his celebrated 1921 vagus-stimulation experiment (paraphrase): stimulating the vagus nerve attached to one isolated frog heart caused it to slow, and when the bathing fluid was transferred to a second unstimulated heart, that heart slowed too. Some chemical substance released by the vagus nerve was therefore the active mediator. Loewi named it "Vagusstoff" and it was later identified as acetylcholine — the first known neurotransmitter. Henry Dale (shared 1936 Nobel with Loewi) extended this work by classifying neurones as cholinergic (releasing acetylcholine) or adrenergic (releasing noradrenaline), and characterised receptor subtypes (paraphrase). Bernard Katz (1970 Nobel, shared with Julius Axelrod and Ulf von Euler) developed the vesicle hypothesis of neurotransmitter release using the frog neuromuscular junction: ACh is released in discrete "quanta" corresponding to the contents of single synaptic vesicles, and the trigger for release is Ca²⁺ influx through voltage-gated channels (paraphrase). John Eccles (1963 Nobel, shared with Hodgkin and Huxley) characterised the excitatory and inhibitory post-synaptic potentials (EPSPs and IPSPs) and showed how their summation determines whether the post-synaptic neurone fires (paraphrase). Modern molecular detail — SNARE proteins, synaptotagmin Ca²⁺ sensors, vesicle endocytosis machinery — fills in the mechanism behind Katz's quantal release, but the conceptual framework is his.

Key Definitions:

• Synapse — a junction between two neurones (or between a neurone and an effector) across which signals are transmitted chemically.
• Cholinergic synapse — a synapse that uses acetylcholine (ACh) as its neurotransmitter.
• Pre-synaptic membrane — the membrane of the neurone before the synapse.
• Synaptic cleft — the narrow (~20 nm) gap between the pre- and post-synaptic membranes.
• Post-synaptic membrane — the membrane of the next cell, studded with neurotransmitter receptors.
• EPSP / IPSP — excitatory or inhibitory post-synaptic potential; a small depolarisation or hyperpolarisation of the post-synaptic cell.

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Why Chemical Synapses Exist

You might ask: why don't neurones just link directly? There are two reasons:

1. Directionality. Chemical synapses only allow signals to flow one way (neurotransmitter is only stored in the pre-synaptic terminal and receptors are only on the post-synaptic cell). Electrical (direct) junctions would allow signals in both directions.
2. Integration. A single post-synaptic neurone receives input from hundreds or thousands of pre-synaptic neurones. Its decision to fire depends on summing excitatory and inhibitory inputs. This integrative computation is only possible at chemical synapses.

Chemical synapses therefore make the nervous system more than a simple set of wires: they make it a network capable of decision-making and learning.

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Structure of a Cholinergic Synapse

A cholinergic synapse has the following features:

• Pre-synaptic knob (terminal bouton): the swollen end of the axon, packed with mitochondria and smooth ER. ATP is needed in abundance for the synthesis, packaging and reuptake of neurotransmitters.
• Synaptic vesicles: small membrane-bound sacs (~40 nm diameter) containing ~10,000 molecules of acetylcholine each.
• Voltage-gated Ca²⁺ channels: in the pre-synaptic membrane; closed at rest.
• Synaptic cleft: ~20 nm wide, filled with extracellular fluid.
• Post-synaptic membrane: with nicotinic acetylcholine receptors, which are ligand-gated sodium channels.
• Acetylcholinesterase (AChE): an enzyme in the cleft or bound to the post-synaptic membrane that rapidly breaks acetylcholine down into choline and ethanoic (acetic) acid.

flowchart LR
    subgraph Pre-synaptic knob
    V[Vesicles with ACh]
    Ca[Voltage-gated Ca2+ channels]
    M[Mitochondria]
    end
    V -->|Exocytosis| C[Synaptic cleft]
    Ca --> V
    C --> R[Nicotinic ACh receptors]
    R --> PM["Post-synaptic membrane<br/>Na+ inflow → EPSP"]
    C --> AE["Acetylcholinesterase<br/>hydrolyses ACh"]
    AE --> CH[Choline + ethanoic acid]
    CH -.reuptake.-> V

Synaptic cleft (~20 nm)

○ ○ ○ ○ ○ ACh diffuses

AChE Post-synaptic cell Nicotinic ACh receptors (ligand-gated Na⁺ channels) → Na⁺ influx → EPSP

Sequence: AP arrives → VGCC open → Ca²⁺ in → vesicle fusion → ACh exocytosed → binds nicotinic receptor → Na⁺ in → EPSP → AChE hydrolyses ACh.

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Step-by-Step Transmission

OCR expects you to describe the following sequence in detail.

1. Action Potential Arrives

An action potential travels down the axon and reaches the pre-synaptic knob, depolarising its membrane.

2. Voltage-Gated Ca²⁺ Channels Open

Depolarisation triggers voltage-gated calcium channels in the pre-synaptic membrane to open. Calcium ions — far more concentrated outside than inside — flow rapidly into the knob down their electrochemical gradient.

3. Vesicles Fuse with the Membrane

The influx of Ca²⁺ triggers vesicles containing acetylcholine to move to and fuse with the pre-synaptic membrane. Vesicles bind to SNARE proteins on the inside of the membrane; calcium acts on synaptotagmin, a calcium sensor, to bring about fusion. (You don't need to name SNAREs or synaptotagmin for OCR, but understanding that Ca²⁺ triggers fusion is essential.)

4. Neurotransmitter Released

Fusion opens the vesicle to the cleft and acetylcholine is released by exocytosis. It diffuses across the cleft (a few microseconds) to the post-synaptic membrane.

5. Receptors Bind ACh — EPSP Produced

Acetylcholine binds to nicotinic acetylcholine receptors, which are ligand-gated sodium channels. Binding opens them, and Na⁺ flows into the post-synaptic cell. This small depolarisation is called an excitatory post-synaptic potential (EPSP).

A single EPSP is typically too small to trigger an action potential on its own. Many EPSPs must sum (see below) to reach threshold.

6. Neurotransmitter Removed

Acetylcholine must be cleared from the cleft rapidly, otherwise every vesicle would trigger sustained stimulation and the synapse would be unable to produce distinct signals. This clearance is performed by acetylcholinesterase (AChE), which hydrolyses ACh into choline and ethanoic (acetic) acid.

7. Reuptake and Resynthesis

Choline is taken back up into the pre-synaptic knob by a transporter. Inside the knob, it is recombined with acetyl-CoA (provided by mitochondria) by the enzyme choline acetyltransferase, regenerating acetylcholine. ACh is packaged into new vesicles, ready to fire again. All of this requires ATP, which is why the pre-synaptic knob has so many mitochondria.

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Summation — How Synapses Integrate

Because a single EPSP is subthreshold, post-synaptic neurones typically receive many synapses simultaneously. Two forms of summation are recognised:

Spatial Summation

Several different pre-synaptic neurones fire at the same time, releasing ACh at multiple synapses onto the same post-synaptic cell. The individual EPSPs add together; if they sum to threshold, an action potential fires. This allows weak inputs from multiple sources to be combined.

Temporal Summation

A single pre-synaptic neurone fires several times in rapid succession. Each impulse produces an EPSP, and because EPSPs last a few milliseconds, overlapping EPSPs sum in time. Again, if the total depolarisation reaches threshold, an action potential fires.

These mechanisms explain why synapses are integrators: they weigh and add inputs, firing only when enough evidence has accumulated.

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Inhibitory Post-Synaptic Potentials (IPSPs)

Not all synapses are excitatory. Some use neurotransmitters such as GABA (gamma-aminobutyric acid — the major inhibitory transmitter of the mammalian brain) or glycine (the dominant inhibitory transmitter of the spinal cord and brainstem) that open Cl⁻ channels or K⁺ channels, hyperpolarising the post-synaptic cell. This is an inhibitory post-synaptic potential (IPSP) and makes it harder to reach threshold. The balance between EPSPs and IPSPs allows fine control: a post-synaptic neurone may be receiving thousands of excitatory inputs but not fire because it is also receiving many inhibitory inputs.

Two mechanisms produce hyperpolarisation at inhibitory synapses:

1. Cl⁻ channel opening (GABA-A receptors, glycine receptors) — Cl⁻ flows into the cell (since [Cl⁻]_out > [Cl⁻]_in), driving the membrane potential towards $E_{Cl}$ECl​ (~−65 mV), which is more negative than the typical −60 mV depolarised firing threshold. Inhibition can be either by hyperpolarisation or by "shunting" — increasing the membrane's conductance and making it harder for excitatory inputs to depolarise the cell.
2. K⁺ channel opening (GABA-B receptors via Gi-protein-coupled second messenger pathway) — K⁺ flows out, driving the membrane towards $E_K$EK​ (~−90 mV) and away from threshold.

The pharmacology of inhibitory synapses is clinically important. Benzodiazepines (diazepam, lorazepam) potentiate GABA-A receptors, increasing inhibition and treating anxiety and seizures. Strychnine blocks glycine receptors, removing inhibition and causing fatal muscle spasms — exploited as a rodenticide. These drugs illustrate how the same logical framework (transmitter → receptor → ion channel → post-synaptic potential) generalises across all chemical synapses.

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Summary of Roles

Component	Role
Voltage-gated Ca²⁺ channels	Allow Ca²⁺ entry on depolarisation; trigger vesicle fusion
Synaptic vesicles	Store and release ACh
Acetylcholine	Excitatory neurotransmitter binding nicotinic receptors
Nicotinic ACh receptors	Ligand-gated Na⁺ channels; produce EPSP
Acetylcholinesterase	Hydrolyses ACh to choline + ethanoic acid, terminating transmission
Choline acetyltransferase	Recycles choline into ACh
Mitochondria	Provide ATP for vesicle loading, pumps and neurotransmitter synthesis

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Drug Action at Synapses

Many drugs and toxins work at synapses — a useful application to mention in exam answers.