GABA facilitates spike propagation through branch points of sensory axons in the spinal cord

Abstract

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.

Altered Regulation of Ia Afferent Input during Voluntary Activity after Human Spinal Cord Injury

“…For decades, it was thought that sensory regulation was accomplished in part through axoaxonic contacts at the terminal of Ia sensory axons through presynaptic inhibition [10][11][12]34 . However, recent evidence in animal and humans suggest that facilitation of Ia mediated EPSPs in motor neurons likely occurs when axon nodes are depolarized from the activation of nodal GABAA receptors 14,15 . Thus, it is possible that the regulation of Ia afferent input tested in our study occurs at different sites within the Ia afferent fiber.…”

“…For decades, it was thought sensory regulation was accomplished in part through axoaxonic contacts at the terminal of Ia sensory axons from GABAergic neurons that receive innervation from the brain and spinal cord through presynaptic inhibition [10][11][12][13] . Recent evidence in animal and humans suggested that facilitation of Ia mediated excitatory postsynaptic potentials (EPSPs) in motor neurons likely occurs when axon nodes are depolarized from the activation of nodal GABAA receptors, which contributes to reduce branch point failure in Ia afferent fibers 14,15 . Thus, GABAergic networks can have both facilitating and inhibitory actions on afferent transmission within the spinal cord at different sites within Ia afferents 16 .…”

The plasticity of nerve fibers: the prolonged effects of polarization of afferent fibers

“…106 and 107). Some of these interneurons were, in addition, found to project to the dorsal columns (102). In view of the growing evidence for nonsynaptically evoked effects of spill-over transmitters (101,(108)(109)(110)(111)(112)(113) and its volume conductance (114,115), these GABAergic interneurons could thereby contribute to changing the excitability of afferent fibers both within and ventral to the dorsal columns.…”

“…. sodium channel clusters were smaller and more closely spaced ($6 mm apart)" (102). The estimated space constant of collaterals of group Ia afferents ($0.1 mm within their proximal compartments (102, see their Supplemental Fig.…”

“…The interest in the excitatory effects of GABA was recently revived by the demonstration that GABA evokes both phasic and tonic depolarization of group Ia afferent fibers and that it may prevent rather than contribute to branch failures and thereby assist the action potential conductance (101,102). The same authors have shown that the phasic increase in the GABA concentration and its release from terminals of dorsal horn GABAergic interneurons (106,118,119) could be evoked within not only the dorsal horn but also the dorsal columns where some of these interneurons were found to project (102; see their Fig.…”