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 An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...

. Presynaptic inhibition occurs when an inhibitory neurotransmitter, like GABA, acts on GABA receptors on the

axon terminal Axon terminals (also called synaptic boutons, terminal boutons, or end-feet) are distal terminations of the telodendria (branches) of an axon. An axon, also called a nerve fiber, is a long, slender projection of a nerve cell, or neuron, that condu ...

. Presynaptic inhibition is ubiquitous among sensory neurons.

Function

Sensory stimuli, such as pain, proprioception, and

somatosensation In physiology, the somatosensory system is the network of neural structures in the brain and body that produce the perception of touch (haptic perception), as well as temperature (thermoception), body position (proprioception), and pain. It is ...

, are sensed by primary afferent fibers.

Somatosensory In physiology, the somatosensory system is the network of neural structures in the brain and body that produce the perception of touch (haptic perception), as well as temperature (thermoception), body position (proprioception), and pain. It is ...

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. 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 The gate control theory of pain asserts that non-painful input closes the nerve "gates" to painful input, which prevents pain sensation from traveling to the central nervous system. The gate control theory of pain describes how non-painful sensatio ...

and gain control-

biological Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up of cells that process hereditary in ...

). 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 Bicuculline is a phthalide-isoquinoline compound that is a light-sensitive competitive antagonist of GABAA receptors. It was originally identified in 1932 in plant alkaloid extracts and has been isolated from ''Dicentra cucullaria'', '' Adlumia ...

, a

GABA receptor agonist A GABA receptor agonist is a drug that is an agonist for one or more of the GABA receptors, producing typically sedative effects, and may also cause other effects such as anxiolytic, anticonvulsant, and muscle relaxant effects. There are three rece ...

). They found that pharmacologically blocking GABA receptors actually enhanced the perception of pain; in other words, GABA usually diminishes the perception of pain. 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, thus supporting a function of presynaptic inhibition as an analgesic. Certain pathological conditions, such as

allodynia Allodynia is a condition in which pain is caused by a stimulus that does not normally elicit pain. For example, bad sunburn can cause temporary allodynia, and touching sunburned skin, or running cold or warm water over it, can be very painful. It i ...

, are thought to be caused by non-modulated

nociceptor A nociceptor ("pain receptor" from Latin ''nocere'' 'to harm or hurt') is a sensory neuron that responds to damaging or potentially damaging stimuli by sending "possible threat" signals to the spinal cord and the brain. The brain creates the sens ...

firing. In addition to dampening pain, impaired presynaptic inhibition has been implicated in many neurological disorders, such as spasticity after spinal cord injury,

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...

autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...

, and fragile-X syndrome.

Mechanisms

Primary sensory afferents contain GABA receptors along their terminals (reviewed in:, Table 1). GABA receptors are

ligand-gated Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in res ...

chloride channels Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration ''in vivo'' is much higher than other anions. Several ...

, formed by the assembly of five

GABA receptor The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the mature vertebrate central nervous system. There are two classes of GABA receptors: GABAA and ...

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 The Na-K-Cl cotransporter (NKCC) is a protein that aids in the secondary active transport of sodium, potassium, and chloride into cells. In humans there are two isoforms of this membrane transport protein, NKCC1 and NKCC2, encoded by two differe ...

) 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 channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...

s 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 channel Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (''e.g.'', muscle, glial cells, neurons, etc.) with a permeabi ...

s, 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

References

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