Presynaptic inhibition

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Presynaptic Inhibition
A circuit diagram of postsynaptic inhibition (A, B) and presynaptic inhibition (C). Excitation is shown in green and inhibition is shown in red.

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.[1]

Function of presynaptic inhibition[edit]

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[2]) 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,[3] 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.[4][5][6][7][8]

Mechanisms of Presynaptic Inhibition & Primary Afferent Depolarization (PAD)[edit]

Primary sensory afferents contain GABA receptors along their terminals (reviewed in:,[9] 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.[10]

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).[11][12] 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:

  1. The depolarized membrane causes inactivation of voltage-gated sodium channels on the terminals and therefore the action potential is prevented from propagating.[9][13][14]
  2. Open GABA receptor channels act as a shunt, whereby current is dissipated of instead of being propagated to the terminals.[9][13][14][15][16][17][18][19][20]
  3. The depolarized membrane causes inactivation of voltage-gated calcium channels, preventing calcium influx at the synapse (which is imperative for neurotransmission).[9][14][16][17][21]
  4. 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.[15]

History of the discovery of presynaptic inhibition[edit]

1933: Grasser & Graham observed depolarization that originated in the sensory axon terminals[22]

1938: Baron & Matthews observed depolarization that originated in sensory axon terminals and the ventral root[23]

1957: Frank & Fuortes coined the term "presynaptic inhibition" [24]

1961: Eccles, Eccles, & Magni determined that the Dorsal Root Potential (DRP) originated from depolarization in sensory axon terminals [25]


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  15. ^ a b Cattaert, D.; Libersat, F.; El Manira A, A. (2001-02-01). "Presynaptic inhibition and antidromic spikes in primary afferents of the crayfish: a computational and experimental analysis". The Journal of Neuroscience. 21 (3): 1007–1021. doi:10.1523/JNEUROSCI.21-03-01007.2001. ISSN 1529-2401. PMC 6762302. PMID 11157086.
  16. ^ a b Panek, Izabela; French, Andrew S.; Seyfarth, Ernst-August; Sekizawa, Shin-ichi; Torkkeli, Päivi H. (July 2002). "Peripheral GABAergic inhibition of spider mechanosensory afferents". The European Journal of Neuroscience. 16 (1): 96–104. doi:10.1046/j.1460-9568.2002.02065.x. ISSN 0953-816X. PMID 12153534. S2CID 20750558.
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  19. ^ Zhang, S. J.; Jackson, M. B. (March 1995). "Properties of the GABAA receptor of rat posterior pituitary nerve terminals". Journal of Neurophysiology. 73 (3): 1135–1144. doi:10.1152/jn.1995.73.3.1135. ISSN 0022-3077. PMID 7608760.
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  22. ^ Gasser & Graham (1933). "Potentials produced in the spinal cord by stimulation of dorsal roots". American Journal of Physiology. 103 (2): 303–320. doi:10.1152/ajplegacy.1933.103.2.303.
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  24. ^ Frank & Fuortes (1957). "Presynaptic and Postsynaptic inhibition of monsynaptic reflexes". Federation Proceedings. 16: 39–40.
  25. ^ Eccles, Eccles, & Magni (1961). "Central inhibitory action attributable to presynaptic depolarization produced by muscle afferent volleys". Journal of Physiology (London). 159: 147–166. doi:10.1113/jphysiol.1961.sp006798. PMC 1359583. PMID 13889050.CS1 maint: multiple names: authors list (link)