Non-classical mechanisms of presynaptic inhibition

Primary afferent neurotransmission is the fundamental first step in the central processing of sensory stimuli. Somatosensory transmission is controlled by a unique ionotropic form of presynaptic inhibition that powerfully limits body sensations. Using multi-pronged approaches that include pioneering electrophysiological studies in the in vitro nerves-attached rodent spinal cord, we are challenging the deeply ingrained doctrine that a 3-synapse circuit with GABAergic interneurons acting on GABAA receptors is responsible. We identified the presence of more direct pathways. We also observed an underlying complex pharmacology that supports promiscuous blending of cys-loop receptors and questions the proprietary role of GABA and GABAA receptors in this process. Cholinergic transmission in particular may contribute significantly, including via direct release from primary afferents. β-alanine and taurine transmission are also implicated.

Shreckengost, J., Calvo, J., Quevedo, J. & Hochman, S. Bicuculline-sensitive primary afferent depolarization remains after greatly restricting synaptic transmission in the mammalian spinal cord. J. Neurosci.,  30(15):5283–5288 (2010).

Hochman, S., Shreckengost, J., Kimura, H., & Quevedo, J. Presynaptic inhibition of primary afferents by depolarization: Observations supporting non-traditional mechanisms. Ann N Y Acad Sci. 1198:140-52, 2010.