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The Journal of Neuroscience, March 1, 2003, 23(5):1832

Perinatal Neurosteroid Levels Influence GABAergic Interneuron Localization in Adult Rat Prefrontal Cortex

A. Chistina Grobin, Erin J. Heenan, Jeffrey A. Lieberman, and A. Leslie Morrow

Departments of Psychiatry and Pharmacology, and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7178

Neurosteroids are a class of steroids synthesized de novo in the brain, several of which are potent modulators of GABA_A receptor function. In developing brain GABA_A receptor, stimulation plays a trophic role. Cortical levels of the GABAergic neurosteroid 3-hydroxy-5-pregnan-20-one (3,5-THP) vary dramatically across development; during the second week of life, elevated levels of 3,5-THP are associated with decreased GABA_A receptor function. To determine whether alteration of endogenous 3,5-THP levels during development alters GABAergic interneurons in prefrontal cortex (PFC) at maturity, rat pups were exposed to 3,5-THP (10 mg/kg) on postnatal day 1 (P1), P2, and P5. On P80, frontal cortex tissue was assayed for GABAergic cell localization (parvalbumin and calbindin immunoreactivity), agonist-dependent [³H] dizocilpine (MK-801) binding to NMDA receptors in cortical homogenates, muscimol-mediated ³⁶Cl influx into synaptoneurosomes, and 3,5-THP levels. The localization of parvalbumin-labeled cells was markedly altered; the ratio of cell number in the deep layers (V-VI) versus superficial layers (I-III) of adult PFC increased twofold in animals exposed to 3,5-THP on P1 or P5. Relative microtubule-associated protein-2 and calbindin immunoreactivity were not altered by perinatal 3,5-THP administration. Agonist-dependent [³H]MK-801 binding was decreased in PFC but not parietal cortex homogenates, whereas muscimol-mediated ³⁶Cl influx and 3,5-THP levels were unchanged in frontal cortex of adult males exposed to 3,5-THP on P5. These data are consistent with a change in the distribution of a subset of interneurons in response to neurosteroid exposure and suggest that GABAergic neurosteroids are critical for normal development of GABAergic systems in the PFC.

Key words: allopregnanolone; calbindin; parvalbumin; schizophrenia; cortical development; stress

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2351832-08$05.00/0

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