A precise balance between excitatory and inhibitory synaptic activity is crucial for the proper function of the six-layered mammalian neocortex, which underlies sensory processing, higher cognition, and regulation of emotions. Cortical inhibitory GABAergic interneurons are central for maintaining this balance by modulating network activity, and disturbances in their development have been linked to a range of neuropsychiatric disorders. Consequently, the identification and characterization of the molecular determinants governing their development is highly relevant for understanding corticogenesis under both physiological and pathological conditions. In contrast to excitatory projection neurons, which are generated within the cortical proliferative zones, interneurons originate in the subpallium and migrate along specific routes through the basal telencephalon into the developing cortex. Within the cortical regions, interneurons distribute tangentially across the intracortical areas before they radially invade the cortical plate, where they undergo morphological maturation and final differentiation into highly diverse subtypes. These primarily encompass parvalbumin (PV)-, somatostatin (SST)-, and vasoactive intestinal peptide (VIP)-expressing cells. The migration and differentiation of cortical interneurons underlie a tightly orchestrated transcriptional machinery, extending beyond interneuron progenitor regulation to postmitotic functions. Epigenetic mechanisms, such as DNA methylation, shape these interneuron-specific intrinsic transcriptional profiles. In this context, the DNA methyltransferase 1 (DNMT1), a key DNA methyltransferase, modulates a broad range of neurodevelopmental processes, including regulating the migration of postmitotic interneurons from the preoptic area (POA). As DNMT1 is also expressed in immature medial ganglionic eminence (MGE)-derived interneurons, the present thesis aimed to examine the role of DNMT1 in migrating SST+ cortical interneurons. To address this, conditional knockout mice with a Dnmt1 deletion restricted to SST+ cells (Sst-Cre/tdTomato/Dnmt1 loxP²) were used to investigate effects on migration and intracortical locomotion at key stages of cortical interneuron development. In SST+ interneurons, DNMT1 was identified to control the transcription of key genes involved in embryonic corticogenesis, specifically those linked to migration, guidance, and intercellular signaling, in a DNA-methylation-dependent manner. In line with the observed changes in gene expression, it was found that the distribution of Dnmt1-KO SST+ interneurons was altered within the cortex of embryonic day (E) 14.5, with fewer KO cells migrating tangentially along the marginal zone (MZ) and, conversely, more cells showing a premature invasion of the cortical plate (CP). Beyond these cell-autonomous effects on interneuron migration, non-cell-autonomous consequences on the local cortical progenitor landscape were detected, potentially mediated by changes in expression of genes involved in cell–cell communication and signaling pathways in Dnmt1-deleted SST+ interneurons. Dnmt1-KO embryos showed atypical progenitor populations at mid-corticogenesis, and increased numbers of deep-layer neurons at later stages, suggesting that DNMT1 loss in SST-expressing interneurons can indirectly influence the development of excitatory lineages and cortical organization. These developmental deviations are in line with observed architectural and functional changes in the adult murine cortex. Moreover, behavioral impairments were revealed for adult Sst-Cre/tdTomato/Dnmt1 loxP² mice. Collectively, the present study identified DNMT1 as a pivotal regulator that synchronizes postmitotic interneuron motility and guidance with cortical progenitor dynamics to ensure proper corticogenesis. In summary, DNMT1 regulates interneuron migration and indirectly shapes excitatory lineage specification and cortical architecture, thereby linking early epigenetic dysregulation to circuit imbalance and neuropsychiatric vulnerability.
Julia Reichard (Thu,) studied this question.