This Program examines the interaction of proliferation and interneuron fate determination in the developing medial ganglionic eminence (MGE), and probes functional consequences of altering interneuron subpopulations. Two broad classes of neurons}}}glutamatergic excitatory and GABAergic inhibitory}}} comprise virtually every neural circuit in cerebral cortex. Their morphology, biochemical constituents, electrophysiological properties and synaptic connections can distinguish a remarkable variety of interneuron subtypes. Despite the importance of these GABAergic cells to brain function, surprisingly little is known about how their production is regulated on a cellular or molecular level. Project 1 (Ross PI) studies the roles of cell cycle constituents in the patterning and function of mammalian brain. They found that two Gl-phase active cyclins, cDI and cD2, are expressed in different progenitor subsets in the MGE where genetic ablation of cD2 produces a loss of cortical PV+ but not SST+ interneurons. Experiments probe the hypothesis that cDI functions primarily to promote asymmetric divisions of radial glial cells (RGCs), some of which generate SST+ interneurons. In contrast, cD2 may promote the symmetric divisions of intermediate progenitor cells (IPCs) that will primarily generate PV+ interneurons Project 2 (Anderson PI) investigates the interacting roles of Notch, Wnt and Shh signaling systems to regulate the number and subtypes of neurons generated from the MGE. They have found that modulation of Notch signaling enhances cD2 expression in dorsal MGE (dMGE) and hypothesize that this will increase PV+ output at the expense of SST+ interneurons. Pilot data implicate interactions between Shh and Wnt signaling regulate Notch activity to impact interneuron production and these relationships will be explored Project 3 (Shi PI) uses in utero intraventricular injection of retroviral fluorescent proteins with state-of- the-art time-lapse videomicroscopy and immunohistochemistry to examine cell intrinsic and extrinsic mechanisms regulating divisions in the MGE. These istudies are heavily integrated with cell cycle and signaling investigations in Projects 1 and 2. Core B (Moore Dir.) will determine the functional significance of selective interneuron deficits that involve different interneuron subtypes and anatomical regions in mouse models generated within the Program. Consequences of interneuron subset loss on behavior, brain structure and physiology are sought. It is widely appreciated that key signaling pathways like Notch, Shh, and Wnt and cell cycle regulators like D-cyclins extensively interact to regulate neuronal generation and fate. However the complexity of the interactions, diversity of ventral forebrain-derived neuronal fates and challenges for gene manipulation in this region pose major impediments to comprehensive study in the MGE. This Program tackles this complexity through the combined efforts of 4 Pis using cutting edge approaches to the elucidation of how developmental signals regulate fate and output of these critically important neurons.
Interneuron deficits have been implicated in the pathobiology of major neurological and psychiatric illnesses, including epilepsy, anxiety disorders, autism and schizophrenia. While a great deal has been learned over the last 20 years about proliferation of excitatory, glutamatergic precursors in cortex, a number of challenges have slowed the pace of discovery for studies of the ventral niches that generate interneurons. This Program strives to address this knowledge gap and our work over the past 4 years positions us well to succeed.
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