Source: Discussion 2, Lecture 6
Tags: synapse, chemical synapse, electrical synapse, gap junction, neurotransmitter, glutamate, GABA, acetylcholine, ionotropic receptor, metabotropic receptor, EPSP, IPSP, synaptic transmission, vesicle, SNARE complex, reuptake
This lecture covers how neurons communicate once an action potential reaches the axon terminal. Two synapse types exist (electrical and chemical), but chemical synapses dominate in the brain. Neurotransmitter release, receptor binding, and the resulting postsynaptic potentials (EPSPs and IPSPs) are the core mechanisms. Whether a neuron fires depends on the summation of all excitatory and inhibitory inputs at the axon hillock.
Synapse
A connection between a neuron and another cell (neuron, muscle, gland). Mediates communication and stores information encoded in the strength of the connection.
Presynaptic cell
The neuron sending the signal. Releases neurotransmitters from its axon terminals.
Postsynaptic cell
The cell receiving the signal. Typically receives input at dendrites and dendritic spines.
Spines
Small protrusions on dendrites that are the sites of excitatory synaptic connections. Axons do not have spines.
Electrical synapse (gap junction)
A synapse where two neurons are physically linked by connexin channels, forming a direct electrical connection across a ~3 nm gap. Important for synchronising neurons and brain oscillations.
Chemical synapse
A synapse where the presynaptic neuron releases neurotransmitters into the synaptic cleft (~20 nm gap). These bind to receptors on the postsynaptic cell. The majority of synapses in the brain are chemical.
Vesicle
A membrane-bound compartment in the presynaptic terminal that stores neurotransmitters. Vesicles fuse with the terminal membrane during exocytosis, releasing their contents.
SNARE complex
A protein complex that drives the fusion of vesicles with the presynaptic membrane. Activated by calcium binding.
Glutamate
The primary excitatory neurotransmitter in the human brain. Increases the probability of the postsynaptic neuron firing an action potential. Roughly 80% of brain neurons are glutamatergic.
GABA (gamma-aminobutyric acid)
The primary inhibitory neurotransmitter in the human brain. Decreases the probability of the postsynaptic neuron firing. Roughly 20% of brain neurons are GABAergic.
Acetylcholine (ACh)
A neurotransmitter first identified by Henry Dale, following Otto Loewi's demonstration of chemical signalling. Key in the neuromuscular junction and parasympathetic nervous system.
Ionotropic receptor
A ligand-gated ion channel. When a neurotransmitter binds, the channel opens and ions flow through. Fast acting, directly changes membrane voltage.
Metabotropic receptor
A receptor (e.g. GPCR) that, when bound by a neurotransmitter, changes conformation and triggers a signalling cascade involving secondary messengers. Slow acting, longer-lasting, modulatory.
EPSP (excitatory postsynaptic potential)
A small depolarisation of the postsynaptic membrane caused by excitatory input (e.g. glutamate opening Na+/Ca2+ channels). Makes the neuron more likely to fire.
IPSP (inhibitory postsynaptic potential)
A small hyperpolarisation of the postsynaptic membrane caused by inhibitory input (e.g. GABA opening Cl- channels). Makes the neuron less likely to fire.
Based on Golgi's original (and partly correct, in this specific case) reticular idea: some neurons are physically linked.
Cell membranes come within ~3 nm of each other but are not fused
Connexin channels sit on both sides of the gap and bind together, forming a large pore
This creates a transsynaptic electrical junction, essentially an ion channel between two cells
Electrical information flows directly and continuously
Gap junctions are important for synchronising neural activity and generating brain oscillations.
Based on Cajal's neuron doctrine: neurons are individual units that communicate across a junction.
Information does not flow freely; transmission is an active process
The majority of synapses in the brain are chemical
The presynaptic terminal contains vesicles (filled with neurotransmitters) and mitochondria
The postsynaptic membrane (often on spines) is packed with protein receptors and structural proteins
An action potential propagates down the axon to the presynaptic terminal
Depolarisation of the terminal membrane activates voltage-gated Ca2+ channels
Calcium flows into the cell (high Ca2+ concentration outside, low inside)
Ca2+ binds to the SNARE complex, changing its structure
This drives fusion of neurotransmitter-filled vesicles with the terminal membrane (exocytosis)
Neurotransmitters (~30,000 per vesicle, estimated) are released into the synaptic cleft (~20 nm wide)
Neurotransmitters passively diffuse across the cleft and bind to postsynaptic receptors
Receptor binding opens ion channels (ionotropic) or triggers signalling cascades (metabotropic), either depolarising or hyperpolarising the postsynaptic cell
After exocytosis, the vesicle membrane is pinched off and recycled (endocytosis)
Released neurotransmitters must be removed from the cleft to stop signalling. Two main mechanisms:
Reuptake transporters (dominant in the brain): selective transporters on the presynaptic membrane use ATP to pump neurotransmitters back into the presynaptic terminal
Enzymatic degradation (dominant at the neuromuscular junction): enzymes in the synapse break down the neurotransmitter, rendering it inactive
Otto Loewi (1920) used isolated frog hearts to demonstrate chemical transmission:
Electrically stimulated the vagus nerve connected to heart 1, slowing its beat
Transferred the fluid bathing heart 1 to heart 2 (which had no vagus nerve)
Heart 2 also slowed down
Something in the fluid was causing the effect, proving chemical (not purely electrical) signalling. Henry Dale later isolated and identified the molecule as acetylcholine (ACh).
The brain's two primary neurotransmitters exist in a notable relationship: glutamate is converted into GABA by the enzyme glutamic acid decarboxylase.
Glutamate (excitatory): increases firing probability. ~80% of neurons.
GABA (inhibitory): decreases firing probability. ~20% of neurons.
A small percentage of neurons release other neurotransmitters.
Ionotropic receptors (e.g. ligand-gated ion channels)
Neurotransmitter binds, receptor/channel opens, ions flow through
Fast acting, directly changes voltage
Example: ionotropic glutamate receptors open channels for Na+ and Ca2+
Metabotropic receptors (e.g. GPCRs)
Neurotransmitter binds, receptor changes conformation
Triggers a signal cascade involving secondary messengers
Slow acting, longer response, modulatory effect
Ionotropic glutamate receptors open channels for Na+ and Ca2+:
Na+ flows into the cell, making the membrane less negative (depolarisation)
This is an excitatory postsynaptic potential (EPSP)
The neuron becomes more likely to fire
Ionotropic GABA receptors open channels for Cl-:
Cl- flows into the cell, accumulating negative charge inside
Even though the inside is already negative, low intracellular Cl- concentration drives influx
This is an inhibitory postsynaptic potential (IPSP)
The neuron becomes less likely to fire
Most synapses occur at dendrites
Excitatory synapses are found primarily on dendritic trees (on spines)
Inhibitory synapses also occur at the cell body and terminals
There are very few synapses on axons
All EPSPs and IPSPs are summed at the axon hillock. If the combined signal reaches the action potential threshold, the neuron fires. If not, it does not. This summation is the fundamental computation of the neuron.
⚠️ Know the complete step-by-step sequence from action potential arrival at the terminal through neurotransmitter release and postsynaptic response. This is a very common exam question.
⚠️ Calcium is the trigger for vesicle fusion (via the SNARE complex). No calcium influx, no neurotransmitter release.
⚠️ Understand the difference between ionotropic (fast, direct ion flow) and metabotropic (slow, signalling cascade) receptors.
⚠️ EPSPs depolarise (Na+/Ca2+ influx, more likely to fire). IPSPs hyperpolarise (Cl- influx, less likely to fire). Do not mix these up.
⚠️ Reuptake is the dominant termination mechanism in the brain; enzymatic degradation dominates at the neuromuscular junction.
⚠️ Glutamate is excitatory (~80% of neurons), GABA is inhibitory (~20%). GABA is synthesised directly from glutamate.
⚠️ Spines are on dendrites (postsynaptic, excitatory). Axons do not have spines.
⚠️ Loewi's frog heart experiment is the classic demonstration of chemical (vs electrical) synaptic transmission.
Q: Describe the role of calcium in synaptic transmission.
A: When an action potential depolarises the presynaptic terminal, voltage-gated Ca2+ channels open. Ca2+ flows into the terminal (down its concentration gradient), binds to the SNARE complex, and drives the fusion of neurotransmitter-filled vesicles with the terminal membrane. This releases neurotransmitters into the synaptic cleft.
Q: What is the difference between an electrical synapse and a chemical synapse?
A: Electrical synapses (gap junctions) use connexin channels to directly connect two cells, allowing continuous electrical flow across a ~3 nm gap. Chemical synapses use neurotransmitter release across a ~20 nm cleft to transmit signals; this is an active, regulated process. Most brain synapses are chemical.
Q: How does the postsynaptic neuron "decide" whether to fire an action potential?
A: All excitatory (EPSPs) and inhibitory (IPSPs) inputs are summed at the axon hillock. If the net depolarisation reaches the action potential threshold, the neuron fires. If it does not reach threshold, the neuron does not fire.
Q: Why does GABA cause hyperpolarisation even though the inside of the cell is already negative?
A: GABA opens Cl- channels. Although the inside is already negative, the concentration of Cl- is low inside the cell, so Cl- flows inward down its concentration gradient. This adds negative charge to the interior, making the membrane potential even more negative (hyperpolarisation).
Q: What are the two mechanisms for terminating synaptic transmission, and where is each dominant?
A: Reuptake transporters (dominant in the brain) use ATP to pump neurotransmitters back into the presynaptic terminal. Enzymatic degradation (dominant at the neuromuscular junction) uses enzymes in the cleft to break down the neurotransmitter.
Q: How did Otto Loewi demonstrate that synaptic transmission involves chemical signalling?
A: He stimulated the vagus nerve on an isolated frog heart, slowing it. He then transferred the bathing fluid to a second heart with no vagus nerve attached. The second heart also slowed, proving that a chemical substance (later identified as acetylcholine) was responsible for the signal.
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