Interaction between Genetic Vulnerability and Neurosteroids in Purkinje cells as a Possible Neurobiological Mechanism in Autism Spectrum Disorders

Abstract

Autism has a strong genetic basis, but other risk factors, acting during brain development, probably contribute to the clinical manifestations of the disease. Male sex is an important risk factor in autism, as shown by the much higher frequency of autism in males. Some authors have proposed the theory of the 'autistic brain' as an extreme form of 'male brain.' This theory is supported by the existence of sexual dimorphisms between male and female brains, by the effects of estrogens on several neurotransmitter systems, and by observations that prenatal androgens produce sex differences in brain and behavior. The investigation of sex-related differences in brain structures that are implicated in autism thus appears to be an extremely interesting research avenue. A major challenge, however, is to develop animal models where the interaction between genetic predisposition and non-genetic risk factors in autism can be tested. The heterozygous reeler mouse brain, which has reduced levels of the protein Reelin, reproduces some of the developmental abnormalities observed in the autistic brain, such as loss of Purkinje cells (PCs). It has been demonstrated that male (but not female) heterozygous reeler mice show a loss of PCs in the cerebellum, thus suggesting that decreased function of Reelin in the male gender provides a selective vulnerability to PC loss. Females may be protected against genetic vulnerability because of their high estrogen/androgen balance during brain development. Thus, our efforts are directed toward understanding how male and female sex steroids and Reelin interact during cerebellar development and how they impinge on the regulation of PC generation and survival. This research may define novel targets for therapies to prevent PC loss, with the hypothesis that drugs that prevent or reduce these developmental abnormalities in the animal model may also be useful to prevent or ameliorate autistic behaviors in humans. (PsycINFO Database Record (c) 2016 APA, all rights reserved)