Extrasynaptic alpha(5)GABA(A) receptors on proprioceptive afferents produce a tonic depolarization that modulates sodium channel function in the rat spinal cord

摘要

Activation of GABA(A) 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 extra-synaptic GABA receptors on afferents. Thus. we examined extrasynaptic alpha(5)GABA(A) 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 alpha(5)GABA(A) receptors. In all afferents alpha(5)GABA(A) 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 alpha(5)GABA(A) receptors. When recording intracellularly from these afferents, blocking alpha(5)GABA(A) 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 alpha(5)GABA(A) 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 a alpha(5)GABA(A) 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.