Presynaptic inhibition explained

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. Or when endocannabinoids act as retrograde messengers by binding to presynaptic CB1 receptors, thereby indirectly modulating GABA and the excitability of dopamine neurons by reducing it and other presynaptic released neurotransmitters.[1] Presynaptic inhibition is ubiquitous among sensory neurons.[2]

Function

Sensory stimuli, such as pain, proprioception, and somatosensation, are sensed by primary afferent fibers. Somatosensory neurons encode information about the body's current state (e.g. temperature, pain, pressure, position, etc.). For vertebrate animals, these primary afferent fibers form synapses onto the spinal cord, specifically in the dorsal horn area, onto a variety of downstream targets including both excitatory neurons and inhibitory neurons. Synapses between primary afferent fibers and their targets are the first opportunity for sensory information to be modulated.[3] Primary afferent fibers contain many receptors along their projections, making them amenable to complex modulation. The constant influx of environmental stimuli, as sensed by primary afferent fibers, 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 test whether somatosensation, specifically pain, was subjected to inhibition, scientists injected a chemical into the spinal cord of a rodent to block the primary inhibitory neurotransmitter's activity (bicuculline, a GABA receptor agonist[4]). They found that pharmacologically blocking GABA receptors actually enhanced the perception of pain; in other words, GABA usually diminishes the perception of pain.[5]

The method by which GABA modulates synaptic transmission from primary afferent fibers to their downstream targets is disputed (see Mechanisms section below). Regardless of the mechanics, GABA acts in an inhibitory role to reduce the likelihood of primary afferent fiber synaptic release.

Modulating primary afferent fibers is critical to maintain general comfort. One study showed that animals without a specific type of GABA receptor on their nociceptors were hypersensitive to pain,[6] thus supporting a function of presynaptic inhibition as an analgesic. Certain pathological conditions, such as allodynia, are thought to be caused by non-modulated nociceptor firing. In addition to dampening pain, impaired presynaptic inhibition has been implicated in many neurological disorders, such as spasticity after spinal cord injury,[7] epilepsy, autism, and fragile-X syndrome.[8] [9] [10] [11] [12]

Mechanisms

Primary sensory afferents contain GABA receptors along their terminals (reviewed in:,[13] 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.[14]

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).[15] [16] 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.[17] [18]
  2. Open GABA receptor channels act as a shunt, whereby current is dissipated of instead of being propagated to the terminals.[19] [20] [21] [22] [23] [24]
  3. The depolarized membrane causes inactivation of voltage-gated calcium channels, preventing calcium influx at the synapse (which is imperative for neurotransmission).[25]
  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.

History of the discovery of presynaptic inhibition

1933: Grasser & Graham observed depolarization that originated in the sensory axon terminals[26]

1938: Baron & Matthews observed depolarization that originated in sensory axon terminals and the ventral root[27]

1957: Frank & Fuortes coined the term "presynaptic inhibition"[28]

1961: Eccles, Eccles, & Magni determined that the Dorsal Root Potential (DRP) originated from depolarization in sensory axon terminals [29]

Notes and References

  1. Oleson . Erik B. . 2012-01-26 . Endocannabinoids shape accumbal encoding of cue-motivated behavior via CB1 receptor activation in the ventral tegmentum . Neuron . 73 . 2 . 360–373. 10.1016/j.neuron.2011.11.018 . 22284189 . 3269037 .
  2. McGann JP . Presynaptic inhibition of olfactory sensory neurons: new mechanisms and potential functions . Chemical Senses . 38 . 6 . 459–474 . July 2013 . 23761680 . 3685425 . 10.1093/chemse/bjt018 .
  3. Comitato A, Bardoni R . Presynaptic Inhibition of Pain and Touch in the Spinal Cord: From Receptors to Circuits . International Journal of Molecular Sciences . 22 . 1 . 414 . January 2021 . 33401784 . 7795800 . 10.3390/ijms22010414 . free .
  4. Manske RH . The Alkaloids of Fumaraceous Plants: II. Dicentra Cucullaria (L.) Bernh. . September 1932 . Canadian Journal of Research. en. 7. 3. 265–269. 10.1139/cjr32-078. 1932CJRes...7..265M . 1923-4287.
  5. Roberts LA, Beyer C, Komisaruk BR . Nociceptive responses to altered GABAergic activity at the spinal cord . Life Sciences . 39 . 18 . 1667–74 . November 1986 . 3022091 . 10.1016/0024-3205(86)90164-5 .
  6. Price TJ, Cervero F, Gold MS, Hammond DL, Prescott SA . Chloride regulation in the pain pathway . Brain Research Reviews . 60 . 1 . 149–170 . April 2009 . 19167425 . 2903433 . 10.1016/j.brainresrev.2008.12.015 .
  7. Caron. Guillaume. Bilchak. Jadwiga N.. Côté. Marie-Pascale. 2020. Direct evidence for decreased presynaptic inhibition evoked by PBSt group I muscle afferents after chronic SCI and recovery with step-training in rats. The Journal of Physiology. en. 598. 20. 4621–4642. 10.1113/JP280070. 32721039 . 7719595 . 0022-3751.
  8. Deidda G, Bozarth IF, Cancedda L . Modulation of GABAergic transmission in development and neurodevelopmental disorders: investigating physiology and pathology to gain therapeutic perspectives . Frontiers in Cellular Neuroscience . 8 . 119 . 2014 . 24904277 . 4033255 . 10.3389/fncel.2014.00119 . free .
  9. Zeilhofer HU, Wildner H, Yévenes GE . Fast synaptic inhibition in spinal sensory processing and pain control . Physiological Reviews . 92 . 1 . 193–235 . January 2012 . 22298656 . 3590010 . 10.1152/physrev.00043.2010 .
  10. Lee E, Lee J, Kim E . Excitation/Inhibition Imbalance in Animal Models of Autism Spectrum Disorders . Biological Psychiatry . 81 . 10 . 838–847 . May 2017 . 27450033 . 10.1016/j.biopsych.2016.05.011 . free .
  11. D'Hulst C, Kooy RF . The GABAA receptor: a novel target for treatment of fragile X? . Trends in Neurosciences . 30 . 8 . 425–431 . August 2007 . 17590448 . 10.1016/j.tins.2007.06.003 . 7340813 .
  12. Benarroch EE . GABAA receptor heterogeneity, function, and implications for epilepsy . Neurology . 68 . 8 . 612–614 . February 2007 . 17310035 . 10.1212/01.wnl.0000255669.83468.dd . 11101571 .
  13. Guo D, Hu J . Spinal presynaptic inhibition in pain control . Neuroscience . 283 . 95–106 . December 2014 . 25255936 . 10.1016/j.neuroscience.2014.09.032 . free .
  14. Kahle KT, Staley KJ, Nahed BV, Gamba G, Hebert SC, Lifton RP, Mount DB . Roles of the cation-chloride cotransporters in neurological disease . Nature Clinical Practice. Neurology . 4 . 9 . 490–503 . September 2008 . 18769373 . 10.1038/ncpneuro0883 . 15424963 .
  15. Price TJ, Cervero F, Gold MS, Hammond DL, Prescott SA . Chloride regulation in the pain pathway . Brain Research Reviews . 60 . 1 . 149–170 . April 2009 . 19167425 . 2903433 . 10.1016/j.brainresrev.2008.12.015 .
  16. Willis WD . Dorsal root potentials and dorsal root reflexes: a double-edged sword . Experimental Brain Research . 124 . 4 . 395–421 . February 1999 . 10090653 . 10.1007/s002210050637 . 40738560 .
  17. Cattaert D, El Manira A . Shunting versus inactivation: analysis of presynaptic inhibitory mechanisms in primary afferents of the crayfish . The Journal of Neuroscience . 19 . 14 . 6079–6089 . July 1999 . 10407044 . 6783106 . 10.1523/JNEUROSCI.19-14-06079.1999 .
  18. Willis WD . John Eccles' studies of spinal cord presynaptic inhibition . Progress in Neurobiology . 78 . 3–5 . 189–214 . 2006-02-01 . 16650518 . 10.1016/j.pneurobio.2006.02.007 . 38669996 .
  19. Cattaert D, Libersat F, El Manira A . Presynaptic inhibition and antidromic spikes in primary afferents of the crayfish: a computational and experimental analysis . The Journal of Neuroscience . 21 . 3 . 1007–1021 . February 2001 . 11157086 . 6762302 . 10.1523/JNEUROSCI.21-03-01007.2001 .
  20. Panek I, French AS, Seyfarth EA, Sekizawa S, Torkkeli PH . Peripheral GABAergic inhibition of spider mechanosensory afferents . The European Journal of Neuroscience . 16 . 1 . 96–104 . July 2002 . 12153534 . 10.1046/j.1460-9568.2002.02065.x . 20750558 .
  21. French AS, Panek I, Torkkeli PH . Shunting versus inactivation: simulation of GABAergic inhibition in spider mechanoreceptors suggests that either is sufficient . Neuroscience Research . 55 . 2 . 189–196 . June 2006 . 16616790 . 10.1016/j.neures.2006.03.002 . 2099107 .
  22. Miller RJ . Presynaptic receptors . Annual Review of Pharmacology and Toxicology . 38 . 201–227 . 1998 . 9597154 . 10.1146/annurev.pharmtox.38.1.201 .
  23. Zhang SJ, Jackson MB . Properties of the GABAA receptor of rat posterior pituitary nerve terminals . Journal of Neurophysiology . 73 . 3 . 1135–1144 . March 1995 . 7608760 . 10.1152/jn.1995.73.3.1135 .
  24. Zhang SJ, Jackson MB . GABAA receptor activation and the excitability of nerve terminals in the rat posterior pituitary . The Journal of Physiology . 483 . 3 . 583–595 . March 1995 . 7776245 . 1157804 . 10.1113/jphysiol.1995.sp020608 .
  25. Graham B, Redman S . A simulation of action potentials in synaptic boutons during presynaptic inhibition . Journal of Neurophysiology . 71 . 2 . 538–549 . February 1994 . 8176423 . 10.1152/jn.1994.71.2.538 .
  26. Gasser HS, Graham HT . January 1933 . Potentials produced in the spinal cord by stimulation of dorsal roots. American Journal of Physiology. 103. 2. 303–320. 10.1152/ajplegacy.1933.103.2.303.
  27. Barron DH, Matthews BH . The interpretation of potential changes in the spinal cord . The Journal of Physiology . 92 . 3 . 276–321 . April 1938 . 16994975 . 1395290 . 10.1113/jphysiol.1938.sp003603 .
  28. Frank K, Fuortes MG . 1957. Presynaptic and Postsynaptic inhibition of monsynaptic reflexes. Federation Proceedings. 16. 39–40.
  29. Eccles JC, Eccles RM, Magni F . Central inhibitory action attributable to presynaptic depolarization produced by muscle afferent volleys . The Journal of Physiology . 159 . 147–166 . November 1961 . 1 . 13889050 . 1359583 . 10.1113/jphysiol.1961.sp006798 .

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