Prenatal gonadal steroids affect adult spatial behavior, CA1 and CA3 pyramidal cell morphology in rats

The present study assessed whether prenatal androgen and estrogen exposure affected adult spatial learning and hippocampal morphology. Water maze performance, the CA1 and CA3 pyramidal cell field, and the dentate gyrus-granule cell layer (DG-GCL) morphology were assessed at adulthood (70+ days of age) in males, females, androgen-treated (testosterone propionate, TP, or dihydrotestosterone propionate, DHTP) females (2-4 mg/day), estradiol benzoate (EB)-treated females (100 microgram/day), and males treated with the antiandrogen flutamide (8 mg/day). Pregnant rats were injected daily (sc) between Embryonic Day 16 and birth; all pups were delivered by cesarean section. Flutamide-treated males were castrated upon delivery, and adult castrates were used to control for activational effects. Steroid-sensitive sex differences were observed in water maze performance in favor of males. Males had larger CA1 and CA3 pyramidal cell field volumes and soma sizes than females, which were feminized with flutamide treatment. TP and EB, but not DHTP, masculinized CA1 pyramidal cell field volume and neuronal soma size; CA3 was masculinized in both TP- and DHTP-treated females, while EB was ineffective. No effects were observed in cell density, number, or DG-GCL volume or due to adult hormone levels. Thus, prenatal androgens and estrogen influence sex differences in adult spatial navigation and exert differential effects on CA1 and CA3 pyramidal cell morphology. Hence, in addition to the previously reported postnatal component, there is also a prenatal component to the critical period in which gonadal steroids organize the neural mechanisms underlying sex differences in adult spatial ability.