Postpubertal sex differentiation of forebrain structures and functions depend on transforming growth factor-alpha.

Sex- and age-associated deficits in brain structure and behavior are reported in a number of neuropsychiatric disorders. Although genetic and environmental factors are thought to contribute to the pathogenesis, there are only few examples in clinical or experimental systems that have identified specific causes. Here, we report that transforming growth factor-alpha (TGFalpha) may regulate sex- and age-dependent development of forebrain structures and associated neural functions after puberty. Waved-1 (Wa-1) mice inherit an autosomal recessive, spontaneous mutation that results in a postnatal reduction in TGFalpha gene expression. The assessment of forebrain structures using a three-dimensional magnetic resonance microscopy indicated ventricular enlargement and striatal reduction in both male and female Wa-1 adult mice, with Wa-1 males exhibiting a more severe phenotype. In contrast, the hippocampal volume was reduced only in adult Wa-1 males. Similarly, behavioral analyses showed impaired auditory and contextual fear learning in adult Wa-1 males only, whereas abnormal stress response was expressed by both male and female adult Wa-1 mice. Interestingly, all behavioral deficits were absent before full sexual maturation, despite some slight forebrain structural abnormalities. These results suggest that TGFalpha may regulate postpubertal, sex differentiation in ventricular and periventricular anatomy and associated behavior, affecting predominantly males. In particular, the adult male-specific reduction in hippocampal volume may reflect an age- and sex-specific regulation of stress homeostasis and fear learning. Furthermore, a lack of a behavioral phenotype, despite anatomical alterations in peripubertal Wa-1 mice, suggests that analysis of certain neuroanatomical features at puberty may predict neurobehavioral deficits in adulthood.