LUTEINIZING-HORMONE-RELEASING HORMONE (LHRH) NEURONS MAINTAINED IN NASAL EXPLANTS DECREASE LHRH MESSENGER-RIBONUCLEIC-ACID LEVELS AFTER ACTIVATION OF GABA(A) RECEPTORS

Inhibition of the LHRH system appears to play an important role in pre venting precocious activation of the hypothalamic-pituitary-gonadal ax is. Evidence points to gamma-aminobutyric acid (GABA) as the major neg ative regulator of postnatal LHRH neuronal activity. Changes in LHRH m essenger RNA (mRNA) levels after alterations of GABAergic activity hav e been reported in vivo. However, the extent to which GABA acts direct ly on LHRH neurons to effect LHRH mRNA levels has been difficult to as certain. The present work, evaluates the effect of GABAergic activity, via GABA(A) receptors, on LHRH neuropeptide gene expression in LHRH n eurons maintained in olfactory explants generated from E11.5 mouse emb ryos. These explants maintain large numbers of primary LHRH neurons th at migrate from bilateral olfactory pits in a directed manner. Using i n situ hybridization histochemistry and single cell analysis, we repor t dramatic alterations in LHRH mRNA levels. Inhibition of spontaneous synaptic activity by GABA(A) antagonists, bicuculline (10(-5) M) or pi crotoxin (10(-4) M), or of electrical activity by tetrodotoxin (TTX, 1 0(-6) M) significantly increased LHRH mRNA levels. In contrast, LHRH m RNA levels decreased in explants cultured with the GABA(A) receptor ag onist, muscimol (10(-4) M), or KCl (50 mM). The observed responses sug gest that LHRH neurons possess functional pathways linking GABA(A) rec eptors to repression of neuropeptide gene expression and indicate that gene expression in embryonic LHRH neurons, outside the CNS, is highly responsive to alterations in neuronal activity.