Synaptic Transmission

This lesson is mapped to AQA 7402 Section 3.6.2 — synaptic transmission (refer to the official AQA specification document for exact wording). Synapses are the chemical junctions between neurones, or between neurones and effectors. They are the points at which the nervous system performs the computational work that distinguishes it from a passive wire: every decision, every act of selective attention, every memory, every reflex modulation occurs by integration of excitatory and inhibitory signals at synapses. Charles Sherrington's framework of the nervous system as a network of competing excitations and inhibitions remains the conceptual basis of contemporary neuroscience — at A* level you are expected to deploy this framing rather than describe the synapse as a one-step relay.

The discovery that synaptic transmission is chemical rather than electrical is associated with Otto Loewi, whose night-time dream experiment (paraphrased here as his vagus-stimulation perfusion demonstration of an inhibitory chemical messenger released from one frog heart that slowed a second isolated heart) supplied the foundational evidence that what crosses the synapse is a soluble molecule, not a current. Loewi's "Vagusstoff" was later identified as acetylcholine, the prototype neurotransmitter and the focus of A-Level treatment.

Key Definition: A synapse is the junction between two neurones, consisting of the presynaptic membrane, the synaptic cleft (approximately 20 nm wide), and the postsynaptic membrane. Communication across the synapse is usually chemical, involving the release of a neurotransmitter from synaptic vesicles by Ca²⁺-dependent exocytosis.

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Structure of a Cholinergic Synapse

The most commonly studied synapse at A-Level is the cholinergic synapse, which uses acetylcholine (ACh) as its neurotransmitter. The neuromuscular junction is a specialised cholinergic synapse; cholinergic synapses are also found in the brain (basal forebrain), autonomic ganglia, and in parasympathetic effector targets. The key structural components are:

Presynaptic Knob (Synaptic Bouton)

• Swollen end of the presynaptic axon, typically 1–2 µm in diameter.
• Contains many synaptic vesicles (~40 nm diameter), each filled with approximately 10,000 molecules of acetylcholine.
• Rich in mitochondria — these provide ATP for the synthesis of ACh, for the active reuptake of choline, and for the active pumping of Ca²⁺ back out of the bouton after exocytosis.
• Contains voltage-gated calcium ion (Ca²⁺) channels in the presynaptic membrane, opened by the arriving action potential.
• Contains enzymes for synthesising ACh: choline acetyltransferase (ChAT) catalyses the combination of choline (recycled from the cleft) and acetyl coenzyme A (acetyl CoA, sourced from mitochondrial respiration) to form ACh.

Synaptic Cleft

• A narrow gap of approximately 20–30 nm between the presynaptic and postsynaptic membranes.
• Contains the enzyme acetylcholinesterase (AChE), anchored to the postsynaptic membrane (and to the cleft basal lamina at the neuromuscular junction), which hydrolyses ACh after it has acted.
• Filled with extracellular fluid through which ACh diffuses by random thermal motion in under 0.5 ms.

Postsynaptic Membrane

• Contains specific receptor proteins complementary in shape to acetylcholine.
• These receptors are ligand-gated Na⁺ ion channels — when ACh binds, the channel pore opens, allowing Na⁺ to enter the postsynaptic cell.
• At the neuromuscular junction, these are nicotinic cholinergic receptors (named because nicotine binds them); in the parasympathetic effector synapse they are muscarinic (G-protein-coupled, slower onset).

graph TD
    A["Action potential<br/>arrives at presynaptic knob"] --> B["Voltage-gated Ca²⁺ channels open"]
    B --> C["Ca²⁺ enters down gradient"]
    C --> D["Vesicles fuse with presynaptic membrane"]
    D --> E["ACh released by exocytosis<br/>into 20 nm cleft"]
    E --> F["ACh diffuses across cleft<br/>less than 0.5 ms"]
    F --> G["ACh binds to nicotinic receptor"]
    G --> H["Na⁺ channel opens<br/>EPSP generated"]
    H --> I["Threshold reached?"]
    I -->|yes| J["AP fires in postsynaptic neurone"]
    I -->|no| K["Decays / waits for more input"]
    H --> L["AChE hydrolyses ACh"]
    L --> M["Choline reabsorbed via active transport"]
    M --> N["ACh re-synthesised from choline + acetyl CoA"]

    style D fill:#27ae60,color:#fff
    style G fill:#3498db,color:#fff
    style L fill:#e74c3c,color:#fff

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The Sequence of Synaptic Transmission

The following steps describe transmission at a cholinergic synapse and form the backbone of any extended exam response:

1. An action potential arrives at the presynaptic knob, depolarising the presynaptic membrane.

2. Voltage-gated Ca²⁺ channels open in the presynaptic membrane, and Ca²⁺ ions diffuse into the presynaptic knob down their steep electrochemical gradient (Ca²⁺ outside ~2 mM; Ca²⁺ inside ~100 nM at rest, a 20,000-fold gradient).

3. Ca²⁺ causes synaptic vesicles to move to and fuse with the presynaptic membrane. The calcium ions bind to vesicle-associated proteins (the SNARE complex), triggering exocytosis.

4. ACh is released into the synaptic cleft by exocytosis. Approximately 300 vesicles release their contents per action potential at a typical CNS bouton.

5. ACh diffuses across the synaptic cleft (this takes less than 0.5 ms due to the narrow width of the cleft and the small size of the ACh molecule).

6. ACh binds to specific receptors on the postsynaptic membrane. The receptors are nicotinic cholinergic receptors at the neuromuscular junction.

7. The receptor changes shape, opening the associated ligand-gated Na⁺ channel. Na⁺ ions flow into the postsynaptic cell down their electrochemical gradient.

8. The postsynaptic membrane is depolarised, producing a local potential called an excitatory postsynaptic potential (EPSP) of typically 0.5–1 mV per quantum of ACh release.

9. If sufficient EPSPs summate (spatially or temporally) to reach the threshold (~−55 mV) at the axon hillock, an action potential is generated in the postsynaptic neurone.

10. ACh is hydrolysed by the enzyme acetylcholinesterase (AChE) in the synaptic cleft, producing choline and ethanoic acid (acetic acid). AChE is one of the fastest enzymes known — it can hydrolyse approximately 25,000 ACh molecules per second.

11. Choline is reabsorbed into the presynaptic knob by an Na⁺-coupled active transport system and recycled to synthesise more ACh using acetyl CoA from mitochondria, catalysed by ChAT.

12. Ca²⁺ is actively pumped out of the presynaptic knob (or back into intracellular stores), resetting the bouton for the next action potential.

Exam Tip: Learn this sequence thoroughly — exam questions frequently ask you to describe the events at a synapse in order. Always mention Ca²⁺ ions causing vesicle fusion, the role of acetylcholinesterase in removing ACh, and the recycling of choline. An A* discriminator is naming the quantal nature of ACh release (one vesicle = one quantum) and the role of Ca²⁺ as the trigger, not as a structural component of the vesicle.

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Excitatory and Inhibitory Postsynaptic Potentials

Excitatory Postsynaptic Potentials (EPSPs)

• Produced when a neurotransmitter causes the opening of Na⁺ channels (or in some cases mixed cation channels), depolarising the postsynaptic membrane.
• EPSPs make it more likely that an action potential will be generated in the postsynaptic neurone.
• A single EPSP is usually insufficient to reach threshold from the resting potential (~15 mV of depolarisation is required, and a single EPSP delivers only ~0.5–1 mV) — summation is needed.
• ACh (at nicotinic receptors), glutamate (at AMPA / NMDA receptors), and noradrenaline all produce EPSPs in different parts of the nervous system.

Inhibitory Postsynaptic Potentials (IPSPs)

• Produced when a neurotransmitter causes the opening of Cl⁻ channels (chloride ions flow into the cell, hyperpolarising it) or K⁺ channels (potassium ions flow out, hyperpolarising it).
• This makes the inside of the postsynaptic membrane more negative (hyperpolarised, typically toward −80 mV).
• IPSPs make it less likely that an action potential will be generated.
• Example neurotransmitters that produce IPSPs: GABA (gamma-aminobutyric acid) in the brain, and glycine in the spinal cord. Benzodiazepines and barbiturates enhance GABA action at the GABA-A receptor, producing sedation.

The simultaneous presence of EPSPs and IPSPs at a single postsynaptic neurone is the computational substrate of the entire nervous system — Sherrington's "common path" of converging excitatory and inhibitory influences.

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Summation

Because a single EPSP is usually too small to reach threshold, the nervous system uses summation to determine whether an action potential is generated:

Spatial Summation

• EPSPs from several different presynaptic neurones arrive at the postsynaptic membrane at the same time.
• Their individual depolarisations add together at the axon hillock. If the combined depolarisation reaches threshold, an action potential is triggered.
• This allows integration of information from multiple sources — for example, a motor neurone may need converging inputs from spinal reflex circuits, descending corticospinal commands, and proprioceptive feedback before it fires.

Temporal Summation

• One presynaptic neurone fires repeatedly in quick succession, releasing ACh multiple times.
• The EPSPs from successive impulses add together before the previous EPSP has fully decayed (typical EPSP duration ~10–20 ms, so firing at >50 Hz produces robust summation).
• If the accumulated depolarisation reaches threshold, an action potential is generated.
• Temporal summation is how a high-frequency train of stimuli encodes "stronger stimulus" — it converts the frequency code of the action potential train into an analogue voltage at the postsynaptic membrane.

Integration of EPSPs and IPSPs

• A postsynaptic neurone may receive both EPSPs and IPSPs simultaneously from different presynaptic neurones.
• The axon hillock performs an algebraic sum of all the inputs: if the net effect is depolarisation above threshold, an action potential fires; if IPSPs cancel out the EPSPs, no action potential is generated.
• This is how the nervous system makes decisions — it integrates excitatory and inhibitory signals across thousands of synapses on a single neurone. A pyramidal neurone in the cortex may receive ~10,000 synaptic inputs.

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Roles of Synapses

Synapses are essential for nervous system function for several reasons:

1. Unidirectional transmission: Neurotransmitter is only released from the presynaptic side and receptors are only on the postsynaptic side, ensuring impulses travel in one direction only across the synapse (even if the axon itself can in principle conduct in either direction).

2. Amplification (divergence): One presynaptic neurone can stimulate many postsynaptic neurones, amplifying the signal — a single motor neurone may innervate hundreds of muscle fibres.

3. Integration (convergence): Many presynaptic neurones can converge on one postsynaptic neurone, allowing summation and decision-making.

4. Filtering out low-level stimuli: Weak stimuli may not generate enough neurotransmitter to produce sufficient EPSPs for an action potential — threshold acts as a noise filter.

5. Memory and learning: Repeated stimulation of a synapse can strengthen the connection (long-term potentiation, LTP) by increasing the number of postsynaptic AMPA receptors or by enhancing transmitter release. LTP in the hippocampus is widely regarded as the cellular substrate of declarative memory.

6. Protection (via habituation): Continuous, non-harmful stimulation leads to a gradual reduction in transmitter release, preventing wasteful overstimulation and freeing attention for novel inputs.

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Drugs, Toxins, and the Synapse

Many drugs and toxins exert their effects by interfering with synaptic transmission. This is the molecular basis of psychiatric pharmacology, anaesthesia, and many natural toxins:

Substance	Action	Effect
Nerve gas (e.g. sarin)	Inhibits acetylcholinesterase irreversibly	ACh accumulates → continuous stimulation → spastic paralysis, respiratory failure
Curare	Competitive antagonist at nicotinic ACh receptors	Prevents depolarisation → flaccid muscle paralysis
Nicotine	Agonist at nicotinic receptors (mimics ACh)	Stimulates postsynaptic neurone; long-term receptor down-regulation drives addiction
Botulinum toxin (Botox)	Cleaves SNARE proteins; prevents vesicle fusion	No ACh release → muscle relaxation / flaccid paralysis
Organophosphate insecticides	Inhibit acetylcholinesterase	Continuous stimulation → insect death; same mechanism as sarin at sublethal dose in humans
SSRI antidepressants	Block reuptake of serotonin	Serotonin remains in cleft longer → prolonged signalling at 5-HT receptors
Caffeine	Adenosine receptor antagonist	Blocks the inhibitory adenosine signal that normally promotes drowsiness; relevant to RP10 (lesson 7)
Benzodiazepines	Positive allosteric modulator of GABA-A receptor	Enhanced IPSPs → sedation, anxiolysis

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A-Level Deep Dive

Spec mapping

This content sits in AQA 7402 Section 3.6.2 — synaptic transmission, cholinergic synapse, summation, integration, neuromuscular junction (refer to the official AQA specification document for exact wording). Synaptic transmission is one of the highest-yield topics in 7402 and appears every series.

Synoptic links

This lesson connects to:

1. AQA 7402 Section 3.6.2 — action potential (lesson 1 this course): the synapse is the destination of every action potential — the bridge between two excitable cells. The all-or-nothing principle of the axon is converted at the synapse into the graded analogue voltage of the postsynaptic potential, which is then re-converted to a frequency-coded train of APs in the next axon.
2. AQA 7402 Section 3.6.2 — muscle contraction (lesson 3 this course): the neuromuscular junction is a specialised cholinergic synapse; ACh release triggers depolarisation of the sarcolemma, Ca²⁺ release from the sarcoplasmic reticulum, and the actin–myosin cross-bridge cycle.
3. AQA 7402 Section 3.2.3 — transport across membranes (course 2): synaptic vesicle fusion is an exocytotic example of bulk transport; ligand-gated channels are integral membrane proteins. The same membrane principles underpin every step of synaptic transmission.

Mark-scheme literacy

Synaptic-transmission questions split AO marks predictably:

AO	Typical share	Earned by
AO1 (knowledge)	40–50%	Naming structures, listing the 12-step sequence, defining EPSP / IPSP
AO2 (application)	30–40%	Explaining drug effects from mechanism; linking summation to integration
AO3 (analysis / evaluation)	15–25%	Evaluating evolutionary roles of synapses; synthesising integration with reflex behaviour or memory