Activation of microglia and neuronal excitotoxicity are postulated to underlie the neurodegeneration that frequently accompanies systemic ADS. Cannabinoids, drugs given to AIDS patients clinically and widely used illicitly, modulate excitatory neurotransmission and excitotoxicity. This proposal addresses the overall question of how HIV-1 proteins, chemokines, and cannabinoids influence microglial function and glutamatergic synaptic transmission to ultimately affect neuronal survival.
Four specific aims are proposed. 1) HIV-1 proteins and chemokines activate a novel chemokine receptor signaling cascade in microglia. The hypothesis that downstream elements of this cascade provide branch points to modulate specific cellular functions will be tested. The kinases and channels in this cascade may be useful pharmacologic targets for altering the course of HIV-1 associated dementia. 2) Excitotoxic Ca2+ increases degrade the plasma membrane Ca2+ pump in neurons. The hypothesis that loss of Ca2+ pump activity contributes to excitotoxic neurodegeneration and that enhanced Ca2+ efflux is neuroprotective will be tested. The plasma membrane Ca2+ pump may be an important point of cross talk between the necrotic and apoptotic cell death pathways. 3) Cognitive impairment precedes overt neuronal loss in HIV-1 associated dementia. The hypothesis that neurotoxins released by microglia induce a loss of functional synapses will be tested. Synaptic function may be sensitive to lower concentrations of neurotoxins than cell survival. 4) Cannabinoids protect from excitotoxicity, inhibit the formation of new functional synapses and their effects on synaptic transmission desensitize. The hypothesis that withdrawal of cannabinoids from tolerant cultures will reveal compensatory changes in synaptic transmission and endocannabinoid signaling that increase neuronal sensitivity to excitotoxic stimuli will be tested. These studies will clarify the role of endocannabinoids in CNS stress responses and the effects of exogenous cannabinoids on synaptic plasticity. In addition to providing a better understanding of HIV-1 neurotoxicity and its modulation by cannabinoids, these studies will contribute more generally to understanding chemokine function in microglia, the role of Ca2+ clearance in neurotoxicity and the modulation of synaptic function by G-protein-coupled receptors and neurotoxins.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37DA007304-13
Application #
6745900
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Khalsa, Jagjitsingh H
Project Start
1992-03-15
Project End
2009-01-31
Budget Start
2004-03-15
Budget End
2005-01-31
Support Year
13
Fiscal Year
2004
Total Cost
$322,000
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Strehler, Emanuel E; Thayer, Stanley A (2018) Evidence for a role of plasma membrane calcium pumps in neurodegenerative disease: Recent developments. Neurosci Lett 663:39-47
Raybuck, Jonathan D; Hargus, Nicholas J; Thayer, Stanley A (2017) A GluN2B-Selective NMDAR Antagonist Reverses Synapse Loss and Cognitive Impairment Produced by the HIV-1 Protein Tat. J Neurosci 37:7837-7847
Lee, Christine A; Derefinko, Karen J; Davis, Heather A et al. (2017) Cross-lagged relations between motives and substance use: Can use strengthen your motivation over time? Drug Alcohol Depend 178:544-550
Lee, Christine A; Derefinko, Karen J; Milich, Richard et al. (2017) Longitudinal and reciprocal relations between delay discounting and crime. Pers Individ Dif 111:193-198
Ghosh, Biswarup; Green, Matthew V; Krogh, Kelly A et al. (2016) Interleukin-1? activates an Src family kinase to stimulate the plasma membrane Ca2+ pump in hippocampal neurons. J Neurophysiol 115:1875-85
Green, Matthew V; Thayer, Stanley A (2016) NMDARs Adapt to Neurotoxic HIV Protein Tat Downstream of a GluN2A-Ubiquitin Ligase Signaling Pathway. J Neurosci 36:12640-12649
Derefinko, Karen J; Charnigo, Richard J; Peters, Jessica R et al. (2016) Substance Use Trajectories From Early Adolescence Through the Transition to College. J Stud Alcohol Drugs 77:924-935
Chester, David S; DeWall, C Nathan; Derefinko, Karen J et al. (2016) Looking for reward in all the wrong places: dopamine receptor gene polymorphisms indirectly affect aggression through sensation-seeking. Soc Neurosci 11:487-94
Chester, David S; DeWall, C Nathan; Derefinko, Karen J et al. (2015) Monoamine oxidase A (MAOA) genotype predicts greater aggression through impulsive reactivity to negative affect. Behav Brain Res 283:97-101
Krogh, Kelly A; Lyddon, Elizabeth; Thayer, Stanley A (2015) HIV-1 Tat activates a RhoA signaling pathway to reduce NMDA-evoked calcium responses in hippocampal neurons via an actin-dependent mechanism. J Neurochem 132:354-66

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