This is a renewal application of a highly successful project that has previously elaborated postsynaptic regulation of opioid and dopamine receptors. The studies proposed in the renewal will examine also the presynaptic compartment, specifically focusing on Dl-type dopamine receptors that regulate the direct pathway GABAergic output from striatum / nucleus accumbens, and to precise evaluation ofthe regulation of synaptic vesicle exocytosis from axons.
The Specific Aims of the proposed studies are:
Specific Aim 1. Determine whether rapid DIR trafficking events are restricted to the somatodendritic surface or occur also in axons of MSNs.
Specific Aim 2. Define the effects of extracellular DA dynamics and electrical activity on Dl R endocytosis in MSNs.
Specific Aim 3. Identify functional consequences of DIR trafficking on pre- and post- synaptic signaling. The proposed experiments will define the basic properties of dopaminergic regulation ofthe direct pathway, which controls natural motivated behavior and is critical for the reinforcing effects of addictive drugs. The studies also directly test, and mechanistically elucidate, presynaptic regulation by Dl receptors. This is a fundamental area of cellular neuroscience that is may reveal new approaches for manipulating addictive drug action or treating addictive disorders.
Dopamine signaling in medium spiny neurons ofthe striatum control motivation to natural stimuli and mediate the reinforcing effects of addictive drugs. The proposed studies determin how this signaling works, and examines specific hypotheses for how it is regualted by natural stimuli relative to drugs. This may idenfify specific features of addictive drug action for therapeutic targeting.
|Mosharov, Eugene V; Borgkvist, Anders; Sulzer, David (2015) Presynaptic effects of levodopa and their possible role in dyskinesia. Mov Disord 30:45-53|
|Choy, Regina Wai-Yan; Park, Minjong; Temkin, Paul et al. (2014) Retromer mediates a discrete route of local membrane delivery to dendrites. Neuron 82:55-62|
|Tang, Guomei; Gudsnuk, Kathryn; Kuo, Sheng-Han et al. (2014) Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 83:1131-43|
|Tatti, Roberta; Bhaukaurally, Khaleel; Gschwend, Olivier et al. (2014) A population of glomerular glutamatergic neurons controls sensory information transfer in the mouse olfactory bulb. Nat Commun 5:3791|
|Cebrián, Carolina; Zucca, Fabio A; Mauri, Pierluigi et al. (2014) MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat Commun 5:3633|
|Federici, Mauro; Latagliata, Emanuele Claudio; Ledonne, Ada et al. (2014) Paradoxical abatement of striatal dopaminergic transmission by cocaine and methylphenidate. J Biol Chem 289:264-74|
|Irannejad, Roshanak; Kotowski, Sarah J; von Zastrow, Mark (2014) Investigating signaling consequences of GPCR trafficking in the endocytic pathway. Methods Enzymol 535:403-18|
|Tsvetanova, Nikoleta G; von Zastrow, Mark (2014) Spatial encoding of cyclic AMP signaling specificity by GPCR endocytosis. Nat Chem Biol 10:1061-5|
|Di Fiore, Pier Paolo; von Zastrow, Mark (2014) Endocytosis, signaling, and beyond. Cold Spring Harb Perspect Biol 6:|
|Karpowicz Jr, Richard J; Dunn, Matthew; Sulzer, David et al. (2013) APP+, a fluorescent analogue of the neurotoxin MPP+, is a marker of catecholamine neurons in brain tissue, but not a fluorescent false neurotransmitter. ACS Chem Neurosci 4:858-69|
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