Molecular mechanisms of sex-specific deficits in neurodevelopmental disease

ABSTRACT Autism Spectrum Disorder (ASD) and other neurodevelopmental disorders (NDDs) are more prevalent in males, but the molecular mechanisms behind this sex bias are unclear. This proposal investigates how hormones and sex-specific signaling interact in developing behavioral deficits, using mouse models of Coiled-coil and C2 domain containing 1a (Cc2d1a) loss-of-function. Human biallelic null mutations in CC2D1A cause intellectual disability (ID), ASD, and seizures. Male Cc2d1a-deficient mice display behavioral deficits that recapitulate features of ASD (reduced cognition and sociability), which are absent in females. CC2D1A is a signaling scaffold that modulates cyclic AMP (cAMP) signaling, crucial for synaptic plasticity and learning and memory. Our previous research showed sex-specific disruptions in cAMP signaling in the hippocampus of Cc2d1a-deficient males, that could be rescued only in males by modulating cAMP levels. This indicates that CC2D1A loss leads to sex-specific brain signaling deficits affecting cognition and sociability in males only. We hypothesize that gonadal hormones establish these sex-specific signaling deficits upstream of CC2D1A function leading to distinct male and female behavioral outcomes. However, gonadal hormones can act at different developmental stages to establish sex-specific mechanisms with organizational role early after birth and activational (acute) roles after puberty. Early postnatal lethality in global Cc2d1a knockout (KO) mice previously hindered these studies as the two timepoints could not be studied in the same animal. We recently generated a new hypomorphic mouse strain with a 90% reduction in CC2D1A levels that allows hormone modulation at various times during development. Our expertise in CC2D1A function complemental with advice from an expert neuroendocrinologist perfectly position us to conduct the proposed research. In Specific Aim 1, we will determine whether gonadal hormones cause male-specific behavioral deficits in Cc2d1a-deficient mice through organizational or activational action. We will treat female pups with estrogen postnatally to mimic the male testosterone surge and reduce estrogen/testosterone levels in adults via ovariectomy or orchidectomy. In Specific Aim 2, we will probe the molecular mechanism underlying how sex hormones establish sex-specific intracellular signaling in neuronal cultures from Cc2d1a KO and hypomorph mice. This combined approach will These studies will explore a new molecular mechanism for sex-specific cognitive deficits, also informing whether therapeutic approaches should be sex-specific.