Presynaptic inhibition is a phenomenon in which an inhibitory neuron provides synaptic input to the axon of another neuron (axo-axonal synapse) to make it less likely to fire an action potential. Presynaptic inhibition occurs when an inhibitory neurotransmitter, like GABA, acts on GABA receptors on the axon terminal. Presynaptic inhibition is ubiquitous among sensory neurons.
Function of presynaptic inhibition
Somatosensory neurons encode information about the body's current state (e.g. temperature, pain, pressure, position, etc.); this constant influx of information is subject to modulation to enhance or diminish stimuli (see also: gate control theory and gain control-biological). Because there are essentially unlimited stimuli, it is imperative that these signals are appropriately filtered. To diminish certain stimuli, primary afferents receive inhibitory input (likely from GABA, but could also be glycine) which reduce their likelihood of synaptic output. There is evidence to support the hypothesis that presynaptic inhibition functions as an analgesic to relieve pain. When firing of nociceptive (pain-sensing) neurons is reduced, this will also reduce pain perception. One study showed that animals without a specific type of GABA receptor on their nociceptors were hypersensitive to pain, thus supporting an function as an analgesic. In addition to dampening pain, impaired presynaptic inhibition has been implicated in many neurological disorders, such as epilepsy, autism, and fragile-X syndrome.
Mechanisms of Presynaptic Inhibition & Primary Afferent Depolarization (PAD)
Primary sensory afferents contain GABA receptors along their terminals (reviewed in:, Table 1). GABA receptors are ligand-gated chloride channels, formed by the assembly of five GABA receptor subunits. In addition to the presence of GABA receptors along sensory afferent axons, the presynaptic terminal also has a distinct ionic composition that is high in chloride concentration. This is due to cation-chloride cotransporters (for example, NKCC1) that maintain highs intracellular chloride.
Typically when GABA receptors are activated, it causes a chloride influx, which hyperpolarizes the cell. However, in primary afferent fibers, due to the high concentration of chloride at the presynaptic terminal and thus its altered reversal potential, GABA receptor activation actually results in a chloride efflux, and thus a resulting depolarization. This phenomenon is called primary afferent depolarization (PAD). The GABA-induced depolarized potential at afferent axons has been demonstrated in many animals from cats to insects. Interestingly, despite the depolarized potential, GABA receptor activation along the axon still results in a reduction of neurotransmitter release and thus still is inhibitory.
There are four hypotheses which propose mechanisms behind this paradox:
- The depolarized membrane causes inactivation of voltage-gated sodium channels on the terminals and therefore the action potential is prevented from propagating.
- Open GABA receptor channels act as a shunt, whereby current is dissipated of instead of being propagated to the terminals.
- The depolarized membrane causes inactivation of voltage-gated calcium channels, preventing calcium influx at the synapse (which is imperative for neurotransmission).
- The depolarization at the terminals generates an antidromic spike (i.e. an action potential generated in the axon and travels towards the soma), which would prevent orthodromic spikes (i.e. an action potential traveling from the cell's soma toward the axon terminals) from propagating.
History of the discovery of presynaptic inhibition
1933: Grasser & Graham observed depolarization that originated in the sensory axon terminals
1938: Baron & Matthews observed depolarization that originated in sensory axon terminals and the ventral root
1957: Frank & Fuortes coined the term "presynaptic inhibition" 
1961: Eccles, Eccles, & Magni determined that the Dorsal Root Potential (DRP) originated from depolarization in sensory axon terminals 
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