Molecular control of two novel migratory paths for CGE-derived interneurons in the developing mouse brain.

GABAergic interneurons are highly heterogeneous and originate in the subpallium mainly from the medial (MGE) and caudal (CGE) ganglionic eminences according to a precise temporal sequence. MGE-derived cells disperse dorsally and migrate towards all regions of the cortex, but little is known about how CGE-derived cells reach their targets during development. Here, we unravel the existence of two novel CGE caudo-rostral migratory streams, one located laterally (LMS) and the other one more medially (MMS), that, together with the well-known caudal migratory stream (CMS), contribute to populate the neocortex, hippocampus and amygdala. These paths appear in a precise temporal sequence and express a distinct combination of transcription factors, such as SP8, PROX1, COUP-TFI and COUP-TFII. By inactivating COUP-TFI in developing interneurons, the lateral and medial streams are perturbed and expression of SP8 and COUP-TFII affected. As a consequence, adult mutant neocortices have laminar-specific alterations of distinct cortical interneuron subtypes. Overall, we propose that the existence of spatially and temporally regulated migratory paths in the subpallium contributes to the laminar distribution and specification of distinct interneuron subpopulations in the adult brain.

Loss of COUP-TFI alters the balance between caudal ganglionic eminence- and medial ganglionic eminence-derived cortical interneurons and results in resistance to epilepsy.

In rodents, cortical interneurons originate from the medial ganglionic eminence (MGE) and caudal ganglionic eminence (CGE) according to precise temporal schedules. The mechanisms controlling the specification of CGE-derived interneurons and their role in cortical circuitry are still unknown. Here, we show that COUP-TFI expression becomes restricted to the dorsal MGE and CGE at embryonic day 13.5 in the basal telencephalon. Conditional loss of function of COUP-TFI in subventricular precursors and postmitotic cells leads to a decrease of late-born, CGE-derived, VIP (vasoactive intestinal peptide)- and CR (calretinin)-expressing bipolar cortical neurons, compensated by the concurrent increase of early-born MGE-derived, PV (parvalbumin)-expressing interneurons. Strikingly, COUP-TFI mutants are more resistant to pharmacologically induced seizures, a phenotype that is dependent on GABAergic signaling. Together, our data indicate that COUP-TFI controls the delicate balance between MGE- and CGE-derived cortical interneurons by regulating intermediate progenitor divisions and ultimately affecting the activity of the cortical inhibitory circuitry.