The basal ganglia play an important role in voluntary movement and substance dependence. Excitatory glutamatergic corticostriatal projections from the cerebral cortex innervate the basal ganglia at the striatal medium spiny neuron, which also receives modulatory dopamine projections from midbrain nuclei. Both dopamine and glutamate have been implicated in numerous neuropsychiatric disorders including Parkinson's disease and substance dependence. Using a newly developed imaging technique, we have recently shown that dopamine depresses the release of glutamate from a subset of cortical terminals providing filtering of cortical information to the striatum. We hypothesize that alterations in striatal dopamine release lead to long-term changes in striatal excitation mediated by dopamine receptor hypersensitivity and neuroplasticity. There are three major goals: 1) Using mouse models for dopamine depletion and dopamine excess, we will study the effect of altered dopamine availability on striatal synaptic plasticity, 2) we will define the mechanisms underlying these neuroplastic alterations, and 3) we will determine if drug-induced behaviors are determined by such adaptations. We will utilize a newly developed imaging technique that allows direct visualization of release from corticostriatal presynaptic terminals in murine striatal slice preparations. These optical studies will be integrated with whole-cell patch clamp recordings to delineate the characteristics of the corticostriatal pathway and the effects of dopamine transmission at the medium spiny neuron. In vivo manipulations of transgenic and wild-type mice will provide models with which to investigate synaptic plasticity that occurs with dopamine depletion and dopamine excess. The outcome of these investigations will demonstrate how alterations in dopamine release produce corticostriatal plasticity and show mechanistically how aberrant striatal excitation might lead to certain neuropsychiatric signs and symptoms. This project is expected to provide further insights into pharmacological alternatives for the treatment of movement disorders and addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS060803-05
Application #
8118569
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Talley, Edmund M
Project Start
2007-09-30
Project End
2014-07-31
Budget Start
2011-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$334,425
Indirect Cost
Name
University of Washington
Department
Neurology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Storey, Granville P; Gonzalez-Fernandez, Gabriel; Bamford, Ian J et al. (2016) Nicotine Modifies Corticostriatal Plasticity and Amphetamine Rewarding Behaviors in Mice(1,2,3). eNeuro 3:
Wong, M Y; Borgkvist, A; Choi, S J et al. (2015) Dopamine-dependent corticostriatal synaptic filtering regulates sensorimotor behavior. Neuroscience 290:594-607
Wang, Wengang; Nitulescu, Ioana; Lewis, Justin S et al. (2013) Overinhibition of corticostriatal activity following prenatal cocaine exposure. Ann Neurol 73:355-69
Wang, Wengang; Darvas, Martin; Storey, Granville P et al. (2013) Acetylcholine encodes long-lasting presynaptic plasticity at glutamatergic synapses in the dorsal striatum after repeated amphetamine exposure. J Neurosci 33:10405-26
Quintana, Albert; Sanz, Elisenda; Wang, Wengang et al. (2012) Lack of GPR88 enhances medium spiny neuron activity and alters motor- and cue-dependent behaviors. Nat Neurosci 15:1547-55
Wang, Wengang; Dever, Dennis; Lowe, Janet et al. (2012) Regulation of prefrontal excitatory neurotransmission by dopamine in the nucleus accumbens core. J Physiol 590:3743-69
Wong, Minerva Y; Sulzer, David; Bamford, Nigel S (2011) Imaging presynaptic exocytosis in corticostriatal slices. Methods Mol Biol 793:363-76
Parker, Jones G; Wanat, Matthew J; Soden, Marta E et al. (2011) Attenuating GABA(A) receptor signaling in dopamine neurons selectively enhances reward learning and alters risk preference in mice. J Neurosci 31:17103-12
Beutler, Lisa R; Wanat, Matthew J; Quintana, Albert et al. (2011) Balanced NMDA receptor activity in dopamine D1 receptor (D1R)- and D2R-expressing medium spiny neurons is required for amphetamine sensitization. Proc Natl Acad Sci U S A 108:4206-11
Joshi, Prasad R; Wu, Nan-Ping; André, Véronique M et al. (2009) Age-dependent alterations of corticostriatal activity in the YAC128 mouse model of Huntington disease. J Neurosci 29:2414-27

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