KCC2 MEDIATION OF DIRECTION GABA SWITCH AT PUBERTY

Massachusetts General Hospital, Boston MA

Investigators

Abstract

GABA is the major inhibitory influence upon GnRH secretion in the adult mammal. However, it is strongly facilitatory to GnRH release in prepubertal rats. The mechanism by which the direction of its action is switched is unknown, although evidence suggests an alteration in the CI- reversed potential of the GnRH neuron may be responsible. Recently, activation of the K+/CI-co-transporter KCC2 has been demonstrated by the mechanism by which hippocampal neurons reverse their responsiveness to GABA from excitatory to inhibitory, in the second postnatal week. We propose that KCC2 is activated at puberty in GnRH neurons, a timing which may facilitate synaptogenesis and network formation pre-pubertally and render steroid feedback pathways patent post-pubertally. We plan to investigate the developmental expression of KCC2 in the hypothalamus and in immortalized GnRH neurons; demonstrate the necessity and sufficiency of its expression for an inhibitory response of GnRH to GABA; and examine its regulation by steroid hormones.