We propose to analyze the neural functions of two genes that we previously cloned and have found to be highly expressed in the striatum. CalDAG-GEFI has a highly striatum-enriched expression pattern. CalDAGGEFII is also highly expressed in the striatum but less selectively so. These genes are particularly important to study because they have coding regions for calcium and diacylglycerol binding and also a coding region for a guanine nucleotide exchange factor that targets the Ras superfamily proteins (Rap for CalDAG-GEFI and Ras for CalDAG-GEFII). Ras superfamily proteins have recently been implicated in learning and memory functions at the behavioral level and in neuroplasticity and synaptic functions at the cellular level. Ras superfamily proteins are activated by proteins called GEFs and our proposal thus focuses on potential activators of Rap and Ras in the striatum. We have generated CalDAG-GEFI-/- and CalDAG-GEFI/II-/- mice. Based on our preliminary work on CalDAG-GEFI, we hypothesize that this striatum-enriched gene participates in cellular functions related to learning. To test this overall hypothesis, we have developed four Specific Aims. First, we will assess CalDAG-GEFI-/- and +/+ mice in a series of learning paradigms to test our hypothesis that the knockouts will have a striatum-dependent learning deficit. Second, we will record neural activity in the striatum of the mice both under baseline conditions and during procedural learning to test the hypothesis that the knockout mice have a deficit in learning-related neuroplasticity. Third, we will assess the responses of the CalDAG-GEFI-/- and +/+ mice in experiments designed to test our hypothesis that CalDAG-GEFI-/- mice will exhibit abnormal behavioral and cellular responsively to dopamine-receptor agonist and antagonist drugs. Finally, we will carry out Golgi-like in vivo labeling to test for altered morphology of striatal neurons in the knockout mice, perform experiments with immortalized striatal cell lines and primary striatal cultures, and carry out collaborative electron microscopy to test our hypothesis that CalDAG-GEFI participates in the regulation of aspects of striatal neuron morphology, including synaptic structure and process output. These detailed studies of CalDAG-GEFI will be accompanied by initial characterization of CalDAG-GEFII-/- and CalDAG-GEFI/II-/- mice. The work proposed is highly significant for understanding signaling in key basal ganglia neurons whose function is essential for normal behavior and whose dysfunction leads to major extrapyramidal disorders.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-IFCN-E (04))
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Freund, Lisa S
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Massachusetts Institute of Technology
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United States
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Chen, Yi-Chuan; Kuo, Hsiao-Ying; Bornschein, Ulrich et al. (2016) Foxp2 controls synaptic wiring of corticostriatal circuits and vocal communication by opposing Mef2c. Nat Neurosci 19:1513-1522
Kalueff, Allan V; Stewart, Adam Michael; Song, Cai et al. (2016) Neurobiology of rodent self-grooming and its value for translational neuroscience. Nat Rev Neurosci 17:45-59
Newman, Helen; Liu, Fu-Chin; Graybiel, Ann M (2015) Dynamic ordering of early generated striatal cells destined to form the striosomal compartment of the striatum. J Comp Neurol 523:943-62
Burguière, Eric; Monteiro, Patricia; Mallet, Luc et al. (2015) Striatal circuits, habits, and implications for obsessive-compulsive disorder. Curr Opin Neurobiol 30:59-65
Burguière, Eric; Monteiro, Patrícia; Feng, Guoping et al. (2013) Optogenetic stimulation of lateral orbitofronto-striatal pathway suppresses compulsive behaviors. Science 340:1243-6
Crittenden, Jill R; Graybiel, Ann M (2011) Basal Ganglia disorders associated with imbalances in the striatal striosome and matrix compartments. Front Neuroanat 5:59
Sako, W; Morigaki, R; Kaji, R et al. (2011) Identification and localization of a neuron-specific isoform of TAF1 in rat brain: implications for neuropathology of DYT3 dystonia. Neuroscience 189:100-7
Crittenden, Jill R; Dunn, Denise E; Merali, Farhan I et al. (2010) CalDAG-GEFI down-regulation in the striatum as a neuroprotective change in Huntington's disease. Hum Mol Genet 19:1756-65
Pasvolsky, Ronit; Feigelson, Sara W; Kilic, Sara Sebnem et al. (2007) A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets. J Exp Med 204:1571-82
Bernardi, Bruno; Guidetti, Gianni F; Campus, Francesca et al. (2006) The small GTPase Rap1b regulates the cross talk between platelet integrin alpha2beta1 and integrin alphaIIbbeta3. Blood 107:2728-35

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