Neuronal PAS Domain 1 Protein and Its Hypothetical Relationship to Autism

Abstract

Neuronal PAS domain 1 (NPAS1) was discovered in 1997 as a brain-specific transcription factor first detected at embryonic day 15 of the developing mouse embryo. Its expression was observed to peak in the early post-natal days, and in situ hybridization assays in adult mice revealed expression localized to the cortex, hippocampus, thalamus, hypothalamus and superior colliculus. Subsequent immunohistochemical staining assays employing antibodies to NPAS1 revealed an expression pattern largely restricted to inhibitory neurons in the aforementioned brain regions, as well as localized expression in the subgranular region of the dentate gyrus. NPAS1 and NPAS3 transcription factors are paralogues that have evolved from the Drosophila gene Trachealess. Despite the high homology in their bHLH, PAS-A and PAS-B domains, the NPAS1 and NPAS3 proteins appear to be endowed with diametrically opposing functional properties. Interestingly, a translocation that disrupts the NPAS3 gene has been reported in a family suffering from schizophrenia. NPAS3-deficient mice have been reported to have behavioral abnormalities reminiscent of schizophrenia, as well as a distinct deficit in hippocampal neurogenesis. In contrast, several variations in NPAS1 have been found in autistic children. It was found that NPAS1-deficient mice are born with larger than normal brains that contain an over-abundance of neurons in the cortex, as well as a significant increase in hippocampal neurogenesis. The NPAS1-deficient mice also exhibited enhanced sensitivity to acoustic and tactile stimuli. The behavioral and neuroanatomical phenotypes observed in the NPAS1-deficient mice appear to be reminiscent of phenotypes seen in autistic children.