scholarly journals Extrasynaptic α5GABAA receptors on proprioceptive afferents produce a tonic depolarization that modulates sodium channel function in the rat spinal cord

2018 ◽  
Vol 120 (6) ◽  
pp. 2953-2974 ◽  
Author(s):  
Ana M. Lucas-Osma ◽  
Yaqing Li ◽  
Shihao Lin ◽  
Sophie Black ◽  
Rahul Singla ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Sodium Channel ◽  
Gaba Receptors ◽  
Presynaptic Inhibition ◽  
Primary Afferent Depolarization ◽  
Branch Points ◽  
Synaptic Contacts ◽  
Sensory Axons ◽  
Proprioceptive Afferents ◽  
Afferent Terminals

Activation of GABAA receptors on sensory axons produces a primary afferent depolarization (PAD) that modulates sensory transmission in the spinal cord. While axoaxonic synaptic contacts of GABAergic interneurons onto afferent terminals have been extensively studied, less is known about the function of extrasynaptic GABA receptors on afferents. Thus, we examined extrasynaptic α5GABAA receptors on low-threshold proprioceptive (group Ia) and cutaneous afferents. Afferents were impaled with intracellular electrodes and filled with neurobiotin in the sacrocaudal spinal cord of rats. Confocal microscopy was used to reconstruct the afferents and locate immunolabelled α5GABAA receptors. In all afferents α5GABAA receptors were found throughout the extensive central axon arbors. They were most densely located at branch points near sodium channel nodes, including in the dorsal horn. Unexpectedly, proprioceptive afferent terminals on motoneurons had a relative lack of α5GABAA receptors. When recording intracellularly from these afferents, blocking α5GABAA receptors (with L655708, gabazine, or bicuculline) hyperpolarized the afferents, as did blocking neuronal activity with tetrodotoxin, indicating a tonic GABA tone and tonic PAD. This tonic PAD was increased by repeatedly stimulating the dorsal root at low rates and remained elevated for many seconds after the stimulation. It is puzzling that tonic PAD arises from α5GABAA receptors located far from the afferent terminal where they can have relatively little effect on terminal presynaptic inhibition. However, consistent with the nodal location of α5GABAA receptors, we find tonic PAD helps produce sodium spikes that propagate antidromically out the dorsal roots, and we suggest that it may well be involved in assisting spike transmission in general. NEW & NOTEWORTHY GABAergic neurons are well known to form synaptic contacts on proprioceptive afferent terminals innervating motoneurons and to cause presynaptic inhibition. However, the particular GABA receptors involved are unknown. Here, we examined the distribution of extrasynaptic α5GABAA receptors on proprioceptive Ia afferents. Unexpectedly, these receptors were found preferentially near nodal sodium channels throughout the afferent and were largely absent from afferent terminals. These receptors produced a tonic afferent depolarization that modulated sodium spikes, consistent with their location.

scholarly journals Nodal GABA facilitates axon spike transmission in the spinal cord

2021 ◽  
Author(s):  
Krishnapriya Hari ◽  
Ana M. Lucas-Osma ◽  
Krista Metz ◽  
Shihao Lin ◽  
Noah Pardell ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Gabaergic Neurons ◽  
Branch Points ◽  
Cutaneous Stimulation ◽  
Inhibitory Neurotransmitter ◽  
Axonal Conduction ◽  
Sensory Axons ◽  
Sensory Transmission ◽  
Excitatory Action ◽  
The Many

SUMMARYGABA is an inhibitory neurotransmitter that produces both postsynaptic and presynaptic inhibition. We describe here an opposing excitatory action of GABA that facilitates spike transmission at nodes of Ranvier in myelinated sensory axons in the spinal cord. This nodal facilitation results from axonal GABAA receptors that depolarize nodes toward threshold, enabling spike propagation past the many branch points that otherwise fail, as observed in spinal cords isolated from mice or rats. Activation of GABAergic neurons, either directly with optogenetics or indirectly with cutaneous stimulation, caused nodal facilitation that increased sensory transmission to motoneurons without postsynaptically exciting motoneurons. This increased transmission with optogenetic or cutaneous stimulation also occurred in awake mice and humans. Optogenetic inhibition of GABAergic neurons decreased sensory transmission, implying that axonal conduction relies on GABA. The concept of nodal facilitation likely generalizes to other large axons in the CNS, enabling recruitment of selective branches and functional pathways.

Presynaptic inhibition in the crayfish CNS: pathways and synaptic mechanisms

1985 ◽  
Vol 54 (5) ◽  
pp. 1305-1325 ◽  
Author(s):  
M. D. Kirk
Keyword(s):  
Presynaptic Inhibition ◽  
Escape Behavior ◽  
Lucifer Yellow ◽  
Afferent Input ◽  
Abdominal Ganglion ◽  
Primary Afferent Depolarization ◽  
Direct Stimulation ◽  
Primary Input ◽  
Primary Afferent ◽  
Afferent Terminals

I studied the pathways that produce primary afferent depolarization (PAD) and presynaptic inhibition during crayfish escape behavior. Simultaneous intracellular recordings were obtained from interneurons and primary afferent axons in the neuropil of the sixth abdominal ganglion. In several experiments, a sucrose-gap recording of PAD accompanied the intracellular impalements. I have identified PAD-producing inhibitory interneurons (PADIs) that are fired by a single impulse in the lateral (LG) or medial (MG) giant, escape-command axons; the PADIs appear to be directly responsible for presynaptic inhibition of primary afferent input to identified mechanosensory interneurons. PADI spikes, elicited by injection of depolarizing current, produced unitary PAD with constant short latency (mean = 0.97 +/- 0.12 SD ms). The unitary PADs were capable of following PADI impulses one for one at frequencies greater than 100 Hz, and the amplitude of unitary PAD was increased by injection of chloride into the afferent terminals. Therefore, the PADIs appear to directly produce an increase in chloride conductance in the primary afferent terminals. Intracellular injections of Lucifer yellow or horseradish peroxidase (HRP) revealed three morphological types of PADI. Their axonal branches and terminals are bilateral and overlap extensively with the innervation fields of all 10 sensory roots of the sixth ganglion. The three morphological types of PADI were physiologically indistinguishable. In several cases, the impaled PADI was shown to produce unitary PAD in more than one afferent of a given root as well as in afferents of adjacent roots. Therefore, the PADIs appear to diverge widely and contact many afferents in all of the sixth-ganglion sensory roots. Stimulation, caudal to the fifth ganglion, of an MG that had been interrupted rostral to the fifth ganglion produced no PAD in sixth-ganglion afferents. Also, stimulation of an MG or an LG in a surgically isolated sixth abdominal ganglion failed to produce PAD. Therefore, the pathway between the MGs and PADIs is activated exclusively within the rostral abdominal ganglia. Direct stimulation in the second and third abdominal ganglia of the segmental giants (SGs) produced a polysynaptic, suprathreshold response in the PADIs. This response was compound and was not due to the activity of the identified corollary discharge interneurons, CDI-2 and CDI-3, that are fired by the SGs. Therefore, the primary input to the PADIs must come from other, unidentified CDIs that are driven by the SGs. PADIs were not fired by shocks to the sensory portions of any peripheral roots even though these shocks produced PAD.(ABSTRACT TRUNCATED AT 400 WORDS)

Primary afferent depolarization in frog spinal cord is associated with an increase in membrane conductance

1983 ◽  
Vol 61 (6) ◽  
pp. 626-631 ◽  
Author(s):  
Ante L. Padjen ◽  
Toshio Hashiguchi
Keyword(s):  
Spinal Cord ◽  
Linear Part ◽  
Membrane Conductance ◽  
Potassium Sulfate ◽  
Equilibrium Potential ◽  
Primary Afferent Depolarization ◽  
Primary Afferent ◽  
Frog Spinal Cord ◽  
Voltage Dependent ◽  
Afferent Terminals

The mechanism of primary afferent depolarization (PAD) was studied in the isolated frog spinal cord using intrafibre recording (microelectrodes filled with 0.6 M potassium sulfate) from large myelinated axons of dorsal roots. Standard current–clamp technique was used to obtain voltage–current (V–I) relationship. It was found that: (i) PAD is voltage dependent: its amplitude and rate of rise are increased with hyperpolarization; (ii) the slope of the linear part of the V–I curve obtained during PAD is decreased compared with the V–I curve at rest; (iii) the PAD equilibrium potential, estimated by extrapolation, ranged from −66 to −40 mV. These results suggest that PAD is associated with an increase in conductance of primary afferent terminals and thus seem to provide the first experimental evidence for the hypothesis that shunting of primary afferent membrane is the mechanism of presynaptic inhibition in the vertebrate nervous system.

scholarly journals Stance-phase force on the opposite limb dictates swing-phase afferent presynaptic inhibition during locomotion

2012 ◽  
Vol 107 (11) ◽  
pp. 3168-3180 ◽  
Author(s):  
Heather Brant Hayes ◽  
Young-Hui Chang ◽  
Shawn Hochman
Keyword(s):  
Spinal Cord ◽  
Presynaptic Inhibition ◽  
Stance Phase ◽  
Swing Phase ◽  
Primary Afferent Depolarization ◽  
Environmental Perturbations ◽  
Opposite Limb ◽  
Dorsal Root Potentials ◽  
Powerful Mechanism

Presynaptic inhibition is a powerful mechanism for selectively and dynamically gating sensory inputs entering the spinal cord. We investigated how hindlimb mechanics influence presynaptic inhibition during locomotion using pioneering approaches in an in vitro spinal cord–hindlimb preparation. We recorded lumbar dorsal root potentials to measure primary afferent depolarization-mediated presynaptic inhibition and compared their dependence on hindlimb endpoint forces, motor output, and joint kinematics. We found that stance-phase force on the opposite limb, particularly at toe contact, strongly influenced the magnitude and timing of afferent presynaptic inhibition in the swinging limb. Presynaptic inhibition increased in proportion to opposite limb force, as well as locomotor frequency. This form of presynaptic inhibition binds the sensorimotor states of the two limbs, adjusting sensory inflow to the swing limb based on forces generated by the stance limb. Functionally, it may serve to adjust swing-phase sensory transmission based on locomotor task, speed, and step-to-step environmental perturbations.

scholarly journals Muscle afferent excitability testing in spinal root-intact rats: dissociating peripheral afferent and efferent volleys generated by intraspinal microstimulation

2017 ◽  
Vol 117 (2) ◽  
pp. 796-807 ◽  
Author(s):  
Saeka Tomatsu ◽  
Geehee Kim ◽  
Joachim Confais ◽  
Kazuhiko Seki
Keyword(s):  
Spinal Cord ◽  
Presynaptic Inhibition ◽  
Muscle Afferents ◽  
Primary Afferents ◽  
Medial Gastrocnemius ◽  
Primary Afferent Depolarization ◽  
Spinal Root ◽  
Primary Afferent ◽  
Intraspinal Microstimulation ◽  
Spinal Roots

Presynaptic inhibition of the sensory input from the periphery to the spinal cord can be evaluated directly by intra-axonal recording of primary afferent depolarization (PAD) or indirectly by intraspinal microstimulation (excitability testing). Excitability testing is superior for use in normal behaving animals, because this methodology bypasses the technically challenging intra-axonal recording. However, use of excitability testing on the muscle or joint afferent in intact animals presents its own technical challenges. Because these afferents, in many cases, are mixed with motor axons in the peripheral nervous system, it is crucial to dissociate antidromic volleys in the primary afferents from orthodromic volleys in the motor axon, both of which are evoked by intraspinal microstimulation. We have demonstrated in rats that application of a paired stimulation protocol with a short interstimulus interval (ISI) successfully dissociated the antidromic volley in the nerve innervating the medial gastrocnemius muscle. By using a 2-ms ISI, the amplitude of the volleys evoked by the second stimulation was decreased in dorsal root-sectioned rats, but the amplitude did not change or was slightly increased in ventral root-sectioned rats. Excitability testing in rats with intact spinal roots indicated that the putative antidromic volleys exhibited dominant primary afferent depolarization, which was reasonably induced from the more dorsal side of the spinal cord. We concluded that excitability testing with a paired-pulse protocol can be used for studying presynaptic inhibition of somatosensory afferents in animals with intact spinal roots. NEW & NOTEWORTHY Excitability testing of primary afferents has been used to evaluate presynaptic modulation of synaptic transmission in experiments conducted in vivo. However, to apply this method to muscle afferents of animals with intact spinal roots, it is crucial to dissociate antidromic and orthodromic volleys induced by spinal microstimulation. We propose a new method to make this dissociation possible without cutting spinal roots and demonstrate that it facilitates excitability testing of muscle afferents.

Active-sleep-related suppression of feline trigeminal sensory neurons: evidence implicating presynaptic inhibition via a process of primary afferent depolarization

1996 ◽  
Vol 75 (3) ◽  
pp. 1152-1162 ◽  
Author(s):  
B. E. Cairns ◽  
M. C. Fragoso ◽  
P. J. Soja
Keyword(s):  
Synaptic Transmission ◽  
Presynaptic Inhibition ◽  
Neuron Activity ◽  
Tooth Pulp ◽  
Primary Afferent Depolarization ◽  
Behavioral State ◽  
Active Sleep ◽  
Quiet Sleep ◽  
Primary Afferent ◽  
Afferent Terminals

1. Changes in the excitability of lumbar and trigeminal primary afferent terminals have long been used as an index of primary afferent depolarization (PAD). PAD has been linked in part to the presynaptic inhibition of neurotransmission. During the behavioral state of active sleep, synaptic transmission through the rostral trigeminal sensory nuclear complex (TSNC) is suppressed when compared with other states such as wakefulness or quiet sleep. The mechanism underlying the suppression of neuronal activity in the rostral TSNC during active sleep is not known. Accordingly, experiments were conducted to determine, by examining the excitability of tooth pulp afferent terminals in cat during sleep and wakefulness, whether PAD processes might contribute in part to the suppression of rostral TSNC neuron activity. 2. Unitary potentials recorded in the maxillary canine tooth pulp were evoked by low-intensity stimuli applied to the rostral TSNC. Unitary potentials were identified by their "all-or-nothing" response, their invariant amplitude and latency, and their ability to follow a short train of high-frequency (333 Hz) stimuli. 3. The firing index (FI), a measure of the probability of evoking a unitary potential, was used to assess the changes in excitability of tooth pulp primary afferents. The proximity of stimulating electrodes to the terminal segment rather than a nonterminal segment of a tooth pulp afferent was demonstrated by observing an increase in the FI as a consequence of conditioning stimuli applied to ipsilateral branches of the trigeminal nerves. Increases in the FI over baseline were obtained for conditioning test intervals ranging from 20 to 80 ms, with the peak effect of conditioning occurring at 30 ms. 4. A total of 25 tooth pulp afferent terminals were identified and changes in their FI were examined during wakefulness, quiet sleep, and active sleep. The FI for all 25 terminals during wakefulness (FIW: 0.29 +/- 0.04, mean +/- SE) did not differ from that during quiet sleep (0.32 +/- 0.04). However, when compared with wakefulness, the FI during active sleep (FIAS: 0.52 +/- 0.07) was increased. The mean ratio of change in the FI (FIAS/FIW) was 3.5 +/- 0.9. These findings indicate that, as a population, tooth pulp afferent terminals are depolarized during the state of active sleep and that PAD processes may partly underlie the suppression of synaptic transmission through the rostral TSNC during this state. 5. To explore whether presynaptic excitability changes underlie the modulation of rostral TSNC neuron activity during active sleep, additional experiments were performed in which tooth-pulp-evoked responses of individual rostral TSNC neurons and the FIs of adjacent individual tooth pulp afferent terminals were analyzed as a function of sleep and wakefulness. The results indicated that active-sleep-related PAD was associated with active-sleep-related suppression of tooth-pulp-evoked activity of rostral TSNC neurons. 6. The conclusion is reached that PAD processes contribute to the mechanism whereby synaptic activity through the rostral TSNC is suppressed during the behavioral state of active sleep.

Primary afferent depolarization of C fibres in the spinal cord of the cat

1978 ◽  
Vol 56 (1) ◽  
pp. 154-157 ◽  
Author(s):  
O. Calvillo
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Primary Afferent Depolarization ◽  
Primary Afferent ◽  
Nociceptive Information ◽  
The Central Nervous System ◽  
C Fibre ◽  
Afferent Terminals ◽  
Presynaptic Control ◽  
Terminal Excitability

The excitability of primary afferent terminals of cutaneous C fibres was tested in the spinal cord of decerebrated cats. C fibre terminal excitability was decreased in the spinal state, and increased by conditioning volleys that activated only A fibres of another cutaneous nerve and by stimulating hair mechanically. It is suggested that C fibre input and therefore nociceptive information to the central nervous system is susceptible to presynaptic control by segmental and suprasegmental mechanisms.

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