The loss of synaptic connections correlates with cognitive decline in many neurodegenerative disorders, including HIV-1 associated dementia (HAD). An assay was developed to image intact postsynaptic densities (PSDs) based on detection of clusters of the scaffolding protein PSD95 fused to green fluorescent protein (PSD95-GFP). In hippocampal neurons grown in primary culture, PSD95-GFP puncta were lost following exposure to factors released by HIV-1 infected cells. PSD loss was reversible. Cannabinoids, drugs given to AIDS patients clinically and widely used illicitly, modulate synapse loss.
Three specific aims examine the effects of cannabinoids on the loss and recovery of synapses following exposure to HIV-1 proteins. 1) The hypothesis that neurotoxin-induced synapse loss is a mechanism to reduce excessive glutamatergic stimulation will be tested. These studies will delineate the signaling pathways that lead to synapse loss and cell death providing a foundation from which to study how drugs of abuse affect the balance between synaptic function and neuronal survival. 2) The hypotheses that recovery from synapse loss requires changes in NMDA receptor function and is guided by the location of pre-existing presynaptic terminals will be tested. By determining the mechanisms that initiate and direct the recovery of synapses, these studies will identify sites where cannabinoids might affect the ability of neurons to integrate back into the synaptic network. 3) The effects of acute and chronic exposure to cannabinoids on synaptic changes induced by HIV-1 proteins will be determined. The hypothesis that the mechanism by which cannabinoids modulate synapses depends on the toxic stimulus and the duration of drug treatment will be tested. These studies will provide insight into the processes that underlie cognitive decline in HAD and will enable us to determine the influence of cannabinoids on the balance between network function and cell survival. This project will provide a foundation to guide the development of drugs to improve function in HAD patients and will identify sites where drugs of abuse might interact with the formation and loss of synapses.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Sorensen, Roger
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University of Minnesota Twin Cities
Schools of Medicine
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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
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
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
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
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
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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