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

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 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 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 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 mice, cells that lack NEXMIF have impairments in dendritic arborization and spine development. Remarkably, the NEXMIF-expressing neurons from mice also demonstrate similar defects in dendritic growth and spine formation. These findings establish a novel mouse model of haploinsufficiency and provide new insights into the pathogenesis of -dependent ASD.