ELEVATED VOLTAGE-GATED SODIUM CHANNEL CURRENTS AND ALTERED SYNAPTIC CONNECTIVITY IN AN IN VITRO MODEL OF BIPOLAR DISORDER AND SCHIZOPHRENIA

Common-variant genome-wide association studies for schizophrenia (SCZ) and bipolar disorder (BD) explain limited variance. Two recent exome meta-analyses, SCHEMA and BipEx, revealed ultra-rare loss-of-function (LoF) mutations in genes with odds ratios 5-50, providing high-penetrance entry points for mechanistic study of psychiatric illness. Among these, AKAP11 emerges as shared large-effect risk gene. We hypothesize that AKAP11 loss, a central regulator of PKA, alters neuronal excitability and synaptic development. Using CRISPR/Cas9, we generated heterozygous and homozygous AKAP11 LoF mutations in human embryonic stem cells; parallel CRISPR-interference knock-downs were created in induced pluripotent stem cells. Lines were differentiated into excitatory cortical-like neurons (hNs) by NGN2 overexpression. Whole-cell patch-clamp revealed increased voltage-gated sodium currents (VGNaC) and quantal synaptic properties. Proteomic analysis suggests this VGNaC increase is driven by elevated channel protein levels. Preliminary high-content imaging indicates increased somatodendritic complexity alongside synaptic density deficits. We are currently performing high-throughput physiological measurements, pharmacological experiments, and calcium imaging to explore broader network connectivity. Modeling high-penetrance LoF mutations in hNs has revealed sizeable, directionally consistent alterations in VGNaC and somatodendritic architecture. These phenotypes align with post-mortem reports of reduced synaptic density and perturbed VGNaC expression in patient's cortex. Our isogenic hNs platform effectively bridges genetic findings to cellular pathophysiology, providing a quantitative assay suitable for mechanistic dissection and therapeutic screening.