SEXUALLY DIMORPHIC ROLES OF CORTICAL Β3 INTEGRIN IN ASD AND EPILEPSY

Integrins are biomechanical receptors that physically and functionally link the extracellular matrix (ECM) to the intracellular cytoskeleton, regulating synaptic connectivity and plasticity in response to extracellular cues. In the brain, β3 integrin associates with the αV subunit to form the αVβ3 integrin heterodimer, which mediates adhesion strengthening at excitatory synapses in cortical pyramidal neurons.
Alterations in integrin expression or signalling have been implicated in the aetiology of various brain disorders, including autism spectrum disorder (ASD) and epilepsy, two frequently comorbid conditions. Consistent with this, β3 integrin haplo-insufficiency impairs excitability and synchrony of cortical neuronal networks.
The Itgb3 KO mouse is a well-established model of ASD; however, due to the male-biased prevalence of ASD, the consequences of β3 integrin loss in females remain poorly characterized. Here, we show that female heterozygous and knockout mice exhibit increased seizure susceptibility in the absence of overt social deficits, highlighting sexually dimorphic outcomes of β3 integrin deficiency.
To restore physiological β3 integrin levels, we developed a CRISPRa-based approach to fine-tune expression of endogenous β3 integrin, providing a strategy to modulate cortical activity and seizure susceptibility. Together, these findings highlight sex-specific roles of β3 integrin in cortical function and its contribution to ASD- and epilepsy-related phenotypes.