Sensory neurotransmission is the fundamental first step in the central processing of sensory stimuli. It is controlled by pre- and post-synaptic inhibitory mechanisms. Presynaptic inhibition (PSI) is more powerful than postsynaptic inhibition in depressing the central excitatory actions of almost all primary afferent sensory fibers. A major mechanism producing afferent PSI is via a counterintuitive channel-mediated depolarization of their intraspinal terminals which, conveniently, can be recorded as a dorsal root potential. It is thought that, via a trisynaptic pathway, GABAergic inhibitory interneurons release GABA as the neurotransmitter to produce PSI of large-diameter (low threshold) muscle and cutaneous sensory afferents. However to this day there is little 'squeaky clean'evidence. We have heretical evidence suggesting instead that much of this afferent stimulation-evoked PSI is generated by more direct synaptic pathways that may be;(i) independent of classical GABAA receptors and (ii) independent of GABA. A mechanistic proof of these assertions require a coalescence of pioneering electrophysiological studies in the in vitro nerves-attached mouse spinal cord (P10-14) and includes transgenic lines that identify and knockout specific genes in larger- diameter sensory afferent subpopulation. Specifically, we will test the following two hypotheses: 1. GABA is not the only transmitter producing PSI. Alternates include acetylcholine, taurine and 2-alanine, and these are found in discrete afferent and interneuronal subpopulations. 2. GABAA receptor subunits are not the only subunits in activated receptors. Alternates are nicotinic and glycinergic subunits and these may be assembled in unique heteromeric compositions. If successful, a decades-old view of mechanisms producing PSI will require dramatic conceptual revision. This new perspective broadens our understanding of somatosensory information processing, and may introduce novel control strategies for sensory dysfunction.

Public Health Relevance

We propose to undertake a detailed characterization of the mechanisms responsible for presynaptic inhibition of primary afferents in the mammal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065949-04
Application #
8426151
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Gnadt, James W
Project Start
2010-03-15
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$365,022
Indirect Cost
$123,181
Name
Emory University
Department
Physiology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
García-Ramírez, David L; Calvo, Jorge R; Hochman, Shawn et al. (2014) Serotonin, dopamine and noradrenaline adjust actions of myelinated afferents via modulation of presynaptic inhibition in the mouse spinal cord. PLoS One 9:e89999
Hochman, Shawn; Hayes, Heather Brant; Speigel, Iris et al. (2013) Force-sensitive afferents recruited during stance encode sensory depression in the contralateral swinging limb during locomotion. Ann N Y Acad Sci 1279:103-13
Hayes, Heather Brant; Chang, Young-Hui; Hochman, Shawn (2012) Stance-phase force on the opposite limb dictates swing-phase afferent presynaptic inhibition during locomotion. J Neurophysiol 107:3168-80