c-Maf deletion in cortical somatostatin, but not parvalbumin, interneurons leads to absence-like epileptiform activity in mice

Mafb and c-Maf transcription factors (TFs) are expressed in medial ganglionic eminence (MGE) lineages, beginning in progenitors and continuing into mature GABAergic parvalbumin-positive (PV + ) and somatostatin-positive (SST + ) cortical interneurons (CINs). Deleting Mafb and c-Maf in MGE before SST vs PV fate specification causes developmental anomalies, including altered numbers of CINs and seizure phenotypes, but the specific contributions of these TFs in postmitotic SST + and PV + CINs to epilepsy remain unknown. To address this, we conditionally deleted Mafb or c-Maf in SST + or PV + interneurons after interneuron fate specification in female and male mice. Deletion of c-Maf, but not Mafb, in SST+ cells was associated with reduced synaptic excitation onto these cells and with spontaneous spike-and-wave discharges, consistent with absence-like seizures. In contrast, deletion of Mafb in SST + CINs reduced their density in superficial cortical layers but did not induce epilepsy. Neither c-Maf nor Mafb deletion in PV + CINs produced major electrophysiological or histological abnormalities in the somatosensory cortex. These findings identify a specific requirement for c-Maf in modulating synaptic excitation of SST + interneurons and show that its loss in SST + cells is associated with the development of absence-like epileptiform activity in vivo. Together, our results refine the understanding of how transcriptional programs shape interneuron function in the mature cortex and highlight c-Maf/MAF-dependent pathways as candidates for investigation in epilepsy genetics. Significance Statement Disruptions in cortical circuit development and function are linked to neurodevelopmental disorders. Cortical interneurons (CINs), particularly the two major subtypes—somatostatin-positive (SST + ) and parvalbumin-positive (PV + ) cells—help maintain excitation/inhibition balance. Although Mafb and c-Maf transcription factors are known to regulate CIN development, their roles in mature SST + and PV + cells remain unclear. We show that conditional deletion of c-Maf in postmitotic SST + interneurons alters their synaptic excitation and is associated with the development of spontaneous epileptiform activity in mice. Deletion of either gene in PV + cells had no such effect. These findings reveal a specific vulnerability of SST + cells to c-Maf loss and underscore the need to investigate c-MAF as a potential contributor to epilepsy and related disorders in humans.