Restoration of NEXMIF expression rescues abnormalities in gene transcription, neuron maturation and autistic-like behaviors in Nexmif knockout mice.

NEXMIF is an X-linked gene implicated in encephalopathy with symptoms of autism spectrum disorder (ASD), intellectual disability, and seizures. Our previous work demonstrated that Nexmif knockout (KO) male mice show autistic-like behaviors and memory deficits, accompanied by significant abnormalities in neuronal development and function. However, to date there are no available therapeutics for NEXMIF-related disorders. Here, as a proof-of-concept study, we examined the effect of postnatal reintroduction of the NEXMIF gene as a strategy for rescuing the impaired cellular and behavioral phenotypes in KO mice. We find that injection of a human NEXMIF lentivirus into KO mouse brains at postnatal day 1 (P1) leads to a restoration in synaptic protein expression and formation of dendritic spines. More importantly, postnatal NEXMIF expression ameliorated behavioral defects in repetitive behavior, sociability, social novelty preference, and cognition at adolescent ages, in addition to restoring dysregulated gene expression. These findings suggest that gene reintroduction at a postnatal stage may serve as a rescue strategy for neurodevelopmental and behavioral deficits caused by NEXMIF deficiencies.