Genetic factors involved in the generation and maturation of interneuron diversity within the developing mouse telencephalon

A century ago, our understanding of the brain was limited to descriptions of its gross anatomy. Ramon Y Cajal's recognition that the neuron was the fundamental building block of the brain provided the vital step in beginning a meaningful exploration of how brain structure at a cellular level relates to an organism's ability to manifest complex behaviors. Likely, the telencephalon's capacity to perform a variety of functions relies on its neuronal diversity. Interneurons, with their enormous range of subtypes are ideally suited for this role.;During my PhD, I have studied how both temporal and genetic factors contribute to the generation of interneuron diversity. To examine if/how interneuron diversity is generated over time, I focused on the olfactory bulb, where interneuron production starts during embryogenesis and continues on through adulthood. Using inducible genetic fate mapping of Dlx1/2 precursors, I identified seven olfactory interneuron subtypes and found that the generation of each subpopulation has a unique temporal signature (chapter 2). This study provides the first comprehensive analysis of the temporal generation of olfactory bulb interneuron subtypes and demonstrates that the timing by which these populations are produced is tightly orchestrated.;The remainder of my work has focused on the potential role of intrinsic determinants in generating cortical interneuron diversity. In pursuit of this goal, I conducted a gene expression microarray analysis on cortical interneuron precursors. I focused my analysis on the embryonic ages E13.5 - when interneuron precursors start to invade the cortical plate; and E15.5 - when the vast majority of interneuron precursors have finished their journey into the cortex (chapter 3). In this way, I identified transcription factors, neuropeptides, and cell surface genes whose expression is highly enriched in embryonic cortical interneuron precursors. Surprisingly, I found that subpopulations of migrating cortical interneurons express genes encoding for proteins characteristic of mature interneuron subtypes. These results suggest that interneurons are already relegated to specific genetic subtypes shortly after they become postmitotic.;I further pursued the study of how intrinsic factors determine interneuron fate by analyzing the role of the transcription factor Sox6, using a combination of fate mapping and loss-of-function techniques. In chapter 4 I describe the role of Sox6 in cortical interneuron development, from a cellular to a behavioral level. SOX6 is a protein expressed continuously within MGE-derived cortical interneurons from postmitotic progenitor stages into adulthood. Both its expression pattern and null phenotype suggest that Sox6 gene function is closely linked to that of Lhx6. In Lhx6 and Sox6 null animals, the expression of PV and SST and the position of both basket and Martinotti neurons are abnormal. I found that Sox6 functions downstream of Lhx6. Electrophysiological analysis of Sox6 mutant cortical interneurons revealed that basket cells, even when mispositioned, retain characteristic but immature fast-spiking physiological features. Taken together, these data suggest that Sox6 is not required for the specification of MGE-derived cortical interneurons. This gene is, however, necessary for their normal positioning and maturation. As a consequence, the specific removal of Sox6 from this population results in a severe epileptic encephalopathy.