SLC45A1–HTR2A AXIS DRIVES FEMALE-BIASED CORTICAL E/I IMBALANCE UNDERLYING NEURODEVELOPMENTAL DISORDER PHENOTYPES

Slc45a1 is a proton-coupled glucose transporter recently implicated in neurodevelopmental disorders (NDDs) through several human genetic studies. However, the underlying neurobiological mechanisms remain unclear. Here, we show that Slc45a1 knockout (KO) mice exhibit female-biased behavioral abnormalities modeling core features of NDDs, including reduced social preference, impulsivity, inattention, anxiety, and hyperactivity, accompanied by increased neuronal excitability in the medial prefrontal cortex (mPFC). At the cellular level, Slc45a1 deficiency elevates intracellular pH in dorsal raphe serotonergic neurons, leading to reduced serotonin release in the mPFC. This decrease in serotonergic tone is associated with increased expression of Htr2a, encoding the serotonin receptor 2A (5-HT2A), selectively in female mice. Despite reduced serotonin availability, elevated Htr2a enhances mPFC neuronal activity, as revealed by calcium imaging during optogenetic activation of serotonergic projections. Pharmacological blockade of 5-HT2A signaling with volinanserin normalizes cortical excitation/inhibition balance and rescues multiple NDD-like behavioral phenotypes in female Slc45a1-KO mice. Together, these findings identify a pH-dependent Slc45a1–Htr2a axis that links serotonergic dysfunction to cortical hyperexcitability and female-specific vulnerability to neurodevelopmental disorder–related phenotypes.