As a result of the development of the ability to manipulate Bacterial Artificial Chromosomes (BACs) (Yang et al, 1997), and the large scale application of BAG transgenic mice to map gene expression in the mouse brain (Gong et al, 2003), we are now able to genetically target a large variety of distinct cell types in the striatum and frontal cortex. This capability will be used to study cell specific signal transduction mechanisms, cell specific transcription;)! profiles, and the functional contributions of specific projection neuron populations to behavior in the striatum and frontal cortex in control and neuroleptic drug-treated animals. The experiments to be conducted will be done according to the following Aims:
Aim 1. Preparation of BAC transgenic mice carrying tagged DARPP-32 in specific striatal and cortical cell types. These mice will be used in Project 1 to study cell specific signaling events that directly impinge upon DARPP-32 in animals treated with neuroleptic drugs.
Aim 2. Transcriptional profiling of specific cell types in the striatum and frontal cortex will be studied in normal and drug-treated animals using the BA( array technique. This technique is based on the use of tagged ribosomal proteins to affinity purify polysomal RNA from cellular lysates. It will be utilized for microarray studies of these and other neurons in normal and neuroleptic drug-treated animals. Extension of these studies to frontal cortex will require preparation of BACarray mice targeted to each cortical pyramidal cell type using Drd3, Drd4, Etvl, Epha2, and Elavl4 BAC vectors.
Aim 3. The contributions of specific cell populations to the circuitry and functions of the striatum and prcfrontal cortex will be studied using BAC transgenic mice expressing """"""""tethered toxins"""""""" (Ibancz-Tallon ct al, 2004) in specific striatal and cortical cell types. Collaborative studies with Dr. Surmeier to assess the efficacy of the tethered toxins and their effects on CNS circuitry, and Dr. Nestler to determine their consequences for behavior will be conducted.
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