Relevance of NPAS1/3 balance to autism and schizophrenia
Steven McKnight, Ph.D.
John Rubenstein, M.D., Ph.D.
University of Texas Southwestern Medical Center
Many children with autism have enlarged brains, often caused by an abnormally high density of neurons in the forebrain. Steven McKnight at The University of Texas Southwestern Medical Center and his colleagues hypothesize that defects in the NPAS1 gene, which acts as a brake on the creation of neurons in the developing brain, predispose individuals to autism.
Given that mice with inactivated NPAS1 also have a high density of neurons in their brains, McKnight and colleagues speculate that mutations in NPAS1 lead to autism by allowing neuron production to spiral out of control. The researchers have found mutations in NPAS1 in a small set of individuals with autism, and they propose to build on this finding by sequencing NPAS1 in nearly 3,000 people with the disorder.
Once they identify mutations in NPAS1, the researchers plan to compare the ability of the mutated proteins to form complexes, bind DNA and repress gene expression. They aim to use mice with inactivated NPAS1 to examine the morphology and functioning of neurons in the forebrain, a brain region that mediates the behaviors affected in autism. These studies could lead to experiments in which a handful of the most interesting NPAS1 mutations identified in the clinical samples are recreated in mice, and their impact on neuronal activity and overall behavior is determined.
Another intriguing aspect of NPAS1 is that it may also put the brakes on DNA methylation, a process in which methyl groups are added to DNA to inhibit its transcription. Abnormally high levels of methylation byproducts have been found in individuals with autism. Inactivation of NPAS1, combined with higher use of supplements containing folate and vitamin B1 — required for methylation — by pregnant women in recent decades could be a double whammy that explains the rising rates of autism. The researchers are pursuing this lead by studying the effects of the two nutrients on mice with inactivated NPAS1.