Final Report Summary - ADMIP (Activity-Dependent Maturation of Inhibitory Processing in the Spinal Dorsal Horn) In the early postnatal period neonates are particularly sensitive to touch, often responding with exaggerated reflexes and whole-body movements to an isolated cutaneous stimulus. This suggests a predominance of excitation over inhibition in spinal sensory networks, which may facilitate activity-dependent synaptic strengthening. We have recently shown that neonatal hypersensitivity to touch is due to the late maturation of glycinergic inhibitory signaling and that this signaling, in turn, requires nociceptive activity in the dorsal horn at a critical postnatal period. However, the phenotype of the interneurons involved and the mechanism for their maturation remains to be determined. This project has two primary aims: 1) to test the hypothesis that a specific subpopulation of dorsal horn interneurons is responsible for inhibiting cutaneous tactile sensory input and that their late postnatal maturation contributes to the loss of neonatal tactile hypersensitivity; and 2) to determine the mechanism by which inhibition of low threshold afferent input matures in the spinal dorsal horn. Parvalbumin expressing neurons form a subgroup of inhibitory interneurons that express both GABA and glycine and are involved in the control of innocuous afferent input in the adult dorsal horn making them a key target for this process. We have shown that parvalbumin is not expressed in the dorsal horn until the second postnatal week, coinciding with the behavioural decrease in touch-hypersensitivity. Using cutting edge targeted genetic manipulations and in vivo electrophysiological recordings of dorsal horn neurons, we have identified this restricted population of inhibitory interneurons in the dorsal horn as having a fundamental role in selectively inhibiting dynamic low threshold input, leading to spontaneous pain states when silenced or ablated in the adult mouse. Anatomical connectivity between these cells and within the dorsal horn shifts from predominantly local, to a stronger presynaptic inhibitory drive, suggestive of an activity-dependent re-wiring. In accordance with this, we have identified two separate populations of parvalbumin positive interneurons: one early expressing, presumed presynaptically-targeting dorsal population, and one late-expressing ventrally directed population, which are labelled by the neurotransmitter glycine. From both a technical and scientific perspective, this data is the first to delineate the selective function of an individual population of spinal interneurons using cutting edge intersectional genetic techniques. These intersectional tools are state of the art and have been developed in the Goulding lab, putting this research at the forefront of somatosensory research; using these fine manipulations, subpopulations of spinal parvalbumin interneurons have been selectively targeted and their function altered without the need for surgery or invasive viral injections, allowing the examination of these populations, and their role in acute sensory processing in situ. By providing information on the selective coding and inhibition of innocuous stimulation in the early postnatal period, and the role of late-expressing parvalbumin interneurons in this process, this project will also have social impact, by providing fundamental biological knowledge required for better management of infants in intensive care as well as adults in spontaneous pain states.
