Functional synaptic integration of forebrain GABAergic precursors into the adult spinal cord

Abstract

Spinal cord transplants of embryonic cortical GABAergic progenitor cells derived from the medial ganglionic eminence (MGE) can reverse mechanical hypersensitivity in the mouse models of peripheral nerve injury- and paclitaxel-induced neuropathic pain. Here,we used electrophysiology,immunohistochemistry,and electron microscopy to examine the extent to which MGE cells integrate into host circuitry and recapitulate endogenous inhibitory circuits. Whether the transplants were performed before or after nerve injury,the MGE cells developed into mature neurons and exhibited firing patterns characteristic of subpopulations of cortical and spinal cord inhibitory interneurons. Conversely,the transplanted cells preserved cortical morphological and neurochemical properties. We also observed a robust anatomical and functional synaptic integration of the transplanted cells into host circuitry in both injured and uninjured animals. The MGE cells were activated by primary afferents,including TRPV1-expressing nociceptors,and formed GABAergic,bicuculline-sensitive,synapses onto host neurons. Unexpectedly,MGE cells transplanted before injury prevented the development of mechanical hypersensitivity. Together,our findings provide direct confirmation of an extensive,functional synaptic integration of MGE cells into host spinal cord circuits. This integration underlies normalization of the dorsal horn inhibitory tone after injury and may be responsible for the prophylactic effect of preinjury transplants.