GABAergic neurons regulate nearly all aspects of neural communication and computation in diverse brain regions and circuits. In addition, GABA signaling profoundly influences the development, maturation, and plasticity of the nervous system. GABAergic dysfunctions have been implicated in diseases as diverse as epilepsy, Huntington's disease, autism and schizophrenia. For decades, the heterogeneity and complexity of the GABAergic network has hampered progress in understanding their development and function. Genetically engineered mice provide an ideal system to study the GABAergic neurons, but tools for these studies are thus far limited. What is particularly needed are lines of mice in which genetic manipulations can be performed in specific classes of GABAergic neurons in restricted brain regions during a defined developmental window. We propose to achieve this goal using the Cre-loxP based binary genetic system. In the first two components of this grant (Project A&B), we will generate up to 20 driver lines expressing Cre or inducible form of Cre recombinase in different classes GABAergic neurons and their progenitors. In addition, we will construct a new generation of Cre-activated reporter mice at the Rosa26 locus to achieve high level GFP expression by incorporating the Gal4-UAS amplification cassettes. All driver and reporter lines will be generated in the C57BL/6 strain. In the third component (Project C), we will characterize and validate these driver and reporter lines and establish a web-based platform for disseminating the mice, related reagents, and data obtained from the mice to other investigators. These GABAergic Cre drivers and related reporter lines will significantly accelerate progress in understanding nearly all aspects of the normal development and function of the GABAergic system, and the etiology of a variety of debilitating brain diseases.
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