Questions: Presynaptic Inhibition and Short-Term Synaptic Plasticity

Question 1

Neuron A receives inputs from both neuron B (excitatory) and neuron C (inhibitory). The inhibitory input from C contacts the axon terminal of B directly (axoaxonic synapse), activating GABA-B receptors on B's terminal. What is the immediate consequence for neuron A?

• A. Neuron A is hyperpolarized — it receives a direct inhibitory current from the axoaxonic synapse
• B. Neuron A's input resistance decreases, making it less responsive to all inputs simultaneously
• C. The amount of neurotransmitter released from B onto A is reduced, because GABA-B receptor activation suppresses calcium influx in B's terminal — but A's intrinsic properties are unchanged
• D. Neuron B fires an action potential that propagates to neuron A, but the action potential is smaller in amplitude

Answer: (C)

This is the defining feature of presynaptic inhibition: control at the presynaptic terminal, not at the postsynaptic cell. GABA-B receptors on B's terminal are coupled to potassium channels and calcium channel suppression. Less calcium enters B's terminal → fewer vesicles fuse → less glutamate released onto A. Neuron A receives no direct inhibitory current and its input resistance is unchanged. Compare to postsynaptic inhibition via GABA-A: that would hyperpolarize A (option A) and reduce A's responsiveness to all inputs simultaneously. Presynaptic inhibition is selective — it silences only the B→A pathway, leaving all other inputs to A unaffected.

Question 2

A synapse shows paired-pulse facilitation: the second postsynaptic potential is larger than the first when two stimuli are delivered 20 ms apart. What does this pattern reveal about the synapse's normal release probability?

• A. The synapse has high release probability — the large second response shows robust vesicle replenishment
• B. The synapse has low release probability — residual calcium from the first pulse adds to the second, producing a larger release because there was room to grow
• C. The synapse is undergoing long-term potentiation, and the facilitated response reflects the early phase of LTP
• D. The synapse's readily releasable pool is being replenished between pulses, causing the larger second response

Answer: (B)

Paired-pulse facilitation is diagnostic of low initial release probability. At a low-probability synapse, the first pulse releases few vesicles because calcium triggers only modest fusion. Residual calcium that remains in the terminal after the first pulse adds to the calcium influx from the second pulse, producing a higher peak calcium concentration and more vesicle fusion. Because the initial response was small (few vesicles fused), a large pool of readily-releasable vesicles remains, so the second response can be much larger. High-probability synapses show depression rather than facilitation, because most available vesicles are depleted by the first pulse.

Question 3

Presynaptic inhibition reduces the responsiveness of a neuron to most of its incoming inputs simultaneously, providing global gain control.

• T. True
• F. False

Answer: False

This is false — it describes postsynaptic inhibition, not presynaptic. Presynaptic inhibition acts via axoaxonic synapses on a specific input terminal, reducing transmitter release from that terminal only. The postsynaptic cell's intrinsic properties (input resistance, resting membrane potential, threshold) are unchanged, and all other inputs to the postsynaptic cell remain fully effective. This input-specific selectivity is the key advantage: it allows the nervous system to silence one pathway without broadly suppressing the downstream neuron — a surgical precision that broadband postsynaptic inhibition cannot achieve.

Question 4

Synaptic depression at a high-frequency synapse reflects a malfunction in vesicle replenishment rather than a normal feature of transmission.

• T. True
• F. False

Answer: False

Synaptic depression is a normal, computationally significant feature of high-probability synapses stimulated at high frequency. When each action potential releases a large fraction of the readily releasable vesicle pool, sustained activity depletes vesicles faster than they can be replenished from reserve stores. The result is a decreasing postsynaptic response with successive stimuli. Far from being a failure, this is a low-pass filter: sustained low-frequency inputs are progressively attenuated, while novel bursts stand out. Depression and facilitation together implement different frequency-dependent transformations that are built into the transmission machinery — they are computations, not errors.

Question 5

Explain why presynaptic inhibition provides more surgically precise control than postsynaptic inhibition, and give a physiological context where this precision would be functionally important.

Model answer: Postsynaptic inhibition (e.g., GABA-A receptor activation on the soma or dendrites) injects inhibitory current into the postsynaptic cell, reducing its responsiveness to all inputs by hyperpolarizing it or reducing its input resistance. This is broadband — it gates everything simultaneously. Presynaptic inhibition via axoaxonic synapses targets a single input terminal: only the transmitter release from that specific terminal is reduced, leaving all other inputs to the postsynaptic cell unaffected. In sensory processing, this allows gating of one sensory modality — for example, reducing pain signals from a specific receptor during descending opioid modulation — without suppressing all other somatosensory input to the same spinal neuron.

A classic example occurs in the spinal cord dorsal horn. Primary afferent fibers carrying pain (Aδ and C fibers) can be presynaptically inhibited by interneurons and descending fibers, reducing their transmitter release onto projection neurons. Meanwhile, the projection neuron can still respond normally to non-pain inputs arriving via other terminals. Postsynaptic inhibition of the same projection neuron would indiscriminately block all sensory transmission. The selectivity of presynaptic inhibition makes it the preferred mechanism when modality-specific gating is needed.