Heterozygous Nexmif female mice demonstrate mosaic NEXMIF expression, autism-like behaviors, and abnormalities in dendritic arborization and synaptogenesis

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic basis. ASDs are commonly characterized by impairments in language, restrictive and repetitive behaviors, and deficits in social interactions. Although ASD is a highly heterogeneous disease with many different genes implicated in its etiology, many ASD-associated genes converge on common cellular defects, such as aberrant neuronal morphology and synapse dysregulation. Our previous work revealed that, in mice, complete loss of the ASD-associated X-linked gene NEXMIF results in a reduction in dendritic complexity, a decrease in spine and synapse density, altered synaptic transmission, and ASD-like behaviors. Interestingly, human females of NEXMIF haploinsufficiency have recently been reported to demonstrate autistic features; however, the cellular and molecular basis for this haploinsufficiency-caused ASD remains unclear. Here we report that in the brains of Nexmif^± female mice, NEXMIF shows a mosaic pattern in its expression in neurons. Heterozygous female mice demonstrate behavioral impairments similar to those of knockout male mice. In the mosaic mixture of neurons from Nexmif^± mice, cells that lack NEXMIF have impairments in dendritic arborization and spine development. Remarkably, the NEXMIF-expressing neurons from Nexmif^± mice also demonstrate similar defects in dendritic growth and spine formation. These findings establish a novel mouse model of NEXMIF haploinsufficiency and provide new insights into the pathogenesis of NEXMIF-dependent ASD.