3 alpha-hydroxy-5 alpha-pregnan-20-one levels and GABA(A) receptor-mediated Cl-36(-) flux across development in rat cerebral cortex

Despite considerable evidence showing dramatic changes in the plasticity of GABA(A) receptors during neuronal development and studies showing a direct link between neurosteroid concentrations and alterations in GABA(A) recept or expression, little is known about the role of neurosteroids in GABA(A) r eceptor plasticity early in development. The relationship between changes i n brain concentrations of 3 alpha -hydroxy-5 alpha -pregnan-20-one (allopre gnanolone, 3 alpha ,5 alpha -THP) and GABA(A) receptor function in the brai n during early development was investigated in rats. The concentration in f etal forebrain of the pregnane metabolite 3 alpha ,5 alpha -THP declined pr ecipitously prior to parturition, before returning to normal (adult male) v alues on the day of birth (PO). Postnatal cortical 3 alpha ,5 alpha -THP le vels remain quite low (<2 ng/g) until postnatal day 10 (PD10) and PD14 when we found elevated cortical 3 alpha ,5 alpha -THP levels (3.3 +/-0.8 and 3. 8 +/-0.9 ng/g, respectively). These levels reverted to basal values by PD15 (0.56 +/-0.4 ng/g). We examined GABA(A) receptor-mediated Cl-36(-) flux in cortex of PD7, PD12 and PD16 rat brain. We found a 32% reduction in the st imulation (apparent E-max) of Cl-36(-) uptake by muscimol in PD12 tissue re lative to adult. The potentiating effects of 3 alpha ,21-dihydroxy-5 alpha -pregnane-20-one (tetrahydrodeoxycorticosterone, THDOC) and flunitrazepam w ere decreased in PD12 tissue. These data provide a better understanding of potential contributions endogenous GABAergic neurosteroids may make to norm al neuronal development. (C) 2001 Elsevier Science BY All rights reserved.