Dnmt1-deficiency in PV interneurons alters cortical circuit function and leads to depression-like behavior

Abstract

Neuropsychiatric disorders, including major depressive disorder (MDD), are highly prevalent in modern society, arising from a complex interplay of genetic and environmental factors. Alterations in the function of cortical inhibitory GABAergic interneurons, along with dysregulations of epigenetic signatures and key regulators such as DNA methyltransferase 1 (DNMT1), have been implicated in these conditions. Through its role in catalyzing DNA methylation, DNMT1 modulates the synaptic activity of parvalbumin-expressing (PV) interneurons, which are essential for cortical inhibition. However, the functional consequences of DNMT1 activity in cortical interneurons at the network level and its impact on behavior remain unknown and must be explored to fully understand the disease implications of dysregulated DNMT1 expression and function. To address this, we utilized a conditional knockout mouse model with Dnmt1 deletion in PV interneurons. Our findings reveal that a Dnmt1 deficiency leads to increased spontaneous firing rates of cortical neurons, reduced cortical gamma oscillations, and altered visually evoked neural responses. Despite intact sensory perception, Dnmt1-deficient mice exhibited reduced physical activity, heightened anxiety-like behavior, and signs of anhedonia and apathy, which represent core features of MDD. These results underscore the critical role of DNMT1 in PV interneuron function and identify it as a potential target for MDD research.