<i>Ank3</i> loss in adult forebrain excitatory neurons disrupts behavior, neuronal activity, membrane proteome, and myelination.

Abstract

<i>ANK3</i>, encoding the scaffolding protein ankyrin-G, is a major risk gene for bipolar disorder and schizophrenia, but its cellular and circuit-level mechanisms remain poorly defined. Here, we demonstrate that deletion of <i>Ank3</i> in forebrain excitatory neurons-either prenatally (<i>Ank3^-/^-:Emx1-Cre</i>) or in adolescence (<i>Ank3^-/^-:CaMKIIα-Cre</i>) leads to convergent behavioral phenotypes in adulthood, including hyperactivity, reduced anxiety-like behavior, and decreased depression-like responses. Calcium imaging in cultured neurons and acute brain slices revealed that ankyrin-G loss reduces both spontaneous and evoked neuronal activity. Quantitative proteomic profiling of membrane-enriched cortical fractions uncovered widespread remodeling of the synaptic proteome, including upregulation of the kinase Taok2 and unexpected downregulation of myelin basic protein (Mbp), a structural component of oligodendrocyte-derived myelin. Importantly, chronic lithium treatment, known to reverse behavioral abnormalities in <i>Ank3</i>-deficient mice, also restored Mbp expression. Together, our findings identify ankyrin-G as a molecular bridge between excitatory neuronal activity, synaptic structure, and myelin-associated protein expression, revealing a pathway by which <i>ANK3</i> variants may contribute to neuropsychiatric disease.