Cannabinoid Modulation of Recovery from HIV-Associated Synaptic Toxicity

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DESCRIPTION (provided by applicant): Changes in dendritic morphology such as dendritic pruning precede neuronal cell death in many neurodegenerative disorders, including HIV-1 associated dementia (HAD). The loss of synaptic connections associated with dendritic degeneration correlates with cognitive decline in these disorders. Antiretroviral treatment initially improves neurocognitive function in HAD patients. Preliminary studies quantified intact postsynaptic densities (PSDs) in rat hippocampal neurons grown in primary culture by imaging clusters of the scaffolding protein PSD95 fused to enhanced green fluorescent protein (PSD95-EGFP). This unique imaging based assay enables the number of synaptic connections between the same hippocampal neurons to be recorded over time. HIV-1 proteins and excitotoxins caused significant loss of PSD95-EGFP puncta at concentrations that failed to produce overt neuronal death. PSD loss preceded cell death and was reversible. Synaptic activity is required for the development and stability of synapses and cannabinoids, drugs given to AIDS patients clinically and widely used illicitly, modulate excitatory neurotransmission and excitotoxicity. The hypothesis that cannabinoid agonists slow recovery of synapses following exposure to excitotoxins or HIV proteins will be tested. A detailed time course for recovery of PSD95-EGFP puncta following removal of toxin will be recorded and the effects of pharmacological block of excitatory synaptic transmission determined. A cannabinoid receptor full agonist, the partial agonist ?9-tetrahydrocannabinol and a receptor antagonist will be used to evaluate the role of varying degrees of CB1 receptor activation and endocannabinoid tone on recovery of PSDs. Cannabinoid receptor agonists are predicted to impair the ability of neurons to integrate back into the synaptic network following neurotoxic insult. If cannabinoids inhibit synaptic recovery, these studies would caution against recreational use of cannabinoids or their use as antiemetics and appetite stimulants in patients with HAD. This project may provide a foundation for future studies to evaluate the effects of drugs of abuse on the recovery of neural function following HIV-1 infection of the central nervous system.