Perinatal neurosteroid levels influence GABAergic interneuron localization in adult rat prefrontal cortex.
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 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) vary dramatically across development; during the second week of life, elevated levels of 3alpha,5alpha-THP are associated with decreased GABA(A) receptor function. To determine whether alteration of endogenous 3alpha,5alpha-THP levels during development alters GABAergic interneurons in prefrontal cortex (PFC) at maturity, rat pups were exposed to 3alpha,5alpha-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 [(3)H] dizocilpine (MK-801) binding to NMDA receptors in cortical homogenates, muscimol-mediated (36)Cl(-) influx into synaptoneurosomes, and 3alpha,5alpha-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 3alpha,5alpha-THP on P1 or P5. Relative microtubule-associated protein-2 and calbindin immunoreactivity were not altered by perinatal 3alpha,5alpha-THP administration. Agonist-dependent [(3)H]MK-801 binding was decreased in PFC but not parietal cortex homogenates, whereas muscimol-mediated (36)Cl(-) influx and 3alpha,5alpha-THP levels were unchanged in frontal cortex of adult males exposed to 3alpha,5alpha-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.
Grobin
A Chistina
AC
Department of Psychiatry, and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7178, USA. grobinac@med.unc.edu
Heenan
Erin J
EJ
Lieberman
Jeffrey A
JA
Morrow
A Leslie
AL
D000818:Animals; D000831:Animals, Newborn; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001667:Binding, Competitive / Q000187:drug effects; D002452:Cell Count; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics; D005260:Female; D012739:Gonadal Steroid Hormones / Q000494:pharmacology; D007395:Interneurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D010320:Parvalbumins / Q000378:metabolism; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development; D011280:Pregnanolone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013256:Steroids / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000943:Antigens, Differentiation; D018691:Excitatory Amino Acid Antagonists; D012739:Gonadal Steroid Hormones; D010320:Parvalbumins; D013256:Steroids; D005680:gamma-Aminobutyric Acid; D011280:Pregnanolone