DNMT1-Mediated Regulation of Inhibitory Interneuron Migration Impacts Cortical Architecture and Function

The fine-tuned establishment of neuronal circuits during the formation of the cerebral cortex is pivotal for its functionality. Developmental abnormalities affecting the composition of cortical circuits, which consist of excitatory neurons and inhibitory interneurons, are linked to a spectrum of neuropsychiatric disorders. Excitatory neurons originate in cortical proliferative zones, while inhibitory interneurons migrate from discrete domains of the basal telencephalon into the cortex. This migration is intricately governed by intrinsic genetic programs and extrinsic cues. Our current study reveals the role of the DNA methyltransferase 1 (DNMT1) in controlling expression of key genes implicated in mouse cortical interneuron development and in guiding the migration of somatostatin-expressing interneurons within the developing cortex. Dnmt1 deletion causes interneurons to exit prematurely from the superficial migratory stream. In addition to the perturbed migration pattern and altered gene expression signatures, Dnmt1 -deficient interneurons had a discernible non-cell autonomous effect on cortical progenitors, which culminated in nuanced alterations of layer thicknesses in the adult cortex. Our study reveals that an epigenetic mechanism governs the migration of cortical interneurons and through this, their instructive role in sculpting the intricate cortical layer architecture by signaling to cortical progenitors, with pronounced effects on cortical network function.