Project Details
Description
Summary: HIV-1 Neurotoxicity: Mechanism & Modulation by Cannabinoids
Almost half of HIV-infected individuals experience HIV-associated neurocognitive disorder (HAND) which
manifests as a deterioration of cognitive function; currently, there is no treatment. Our long-term goal is to
inform clinical care of HAND patients by identifying novel neurophysiological changes that underlie HIV-
associated cognitive decline, thereby identifying targets for therapeutic intervention. In the previous funding
period we found that HIV proteins and inflammatory cytokines, factors released by HIV-infected cells, altered
synaptic networks, revealing novel targets for drug development. This new proposal is oriented around
preliminary data describing novel changes in the endocannabinoid (eCB) system during exposure to the HIV
protein Tat. Exposure to Tat impaired eCB-mediated suppression of neurotransmitter release at excitatory but
not inhibitory synapses. The eCB system suppresses aberrant synaptic activity thus, degradation of this
neuroprotective system may exacerbate the synapse loss that correlates with cognitive decline in HAND. The
goal of this proposal is to determine the mechanisms driving changes in eCB signaling during HIV
neurotoxicity and to evaluate the consequences of these changes on network and cognitive function.
In Aim 1 we will determine the mechanism of HIV Tat-induced impairment of the eCB system. We hypothesize
that HIV Tat evokes release of inflammatory cytokines from glia to activate neuronal signaling pathways that
impair cannabinoid type 1 receptor (CB1R)-mediated presynaptic inhibition. Pharmacological and molecular
approaches will be used to determine the contribution of inflammatory cytokines and their downstream
signaling pathways to impaired CB1R function. These studies will provide insight into the cellular actions of the
HIV neurotoxin Tat and have broad implications for the effects of neuroinflammation on the eCB system.
In Aim 2 we will determine how unbalanced eCB signaling affects network activity and cognitive function during
exposure to HIV Tat. We hypothesize that exposure to HIV Tat downregulates CB1R-mediated presynaptic
inhibition at excitatory synapses, thereby increasing vulnerability to excitotoxic synaptic activity. Our hypothesis
predicts that in transgenic mice expressing Tat eCB signaling will be impaired in synaptic recordings from brain
slices, and the loss of eCB signaling will increase the frequency of epileptiform activity detected in EEG
recordings. The contribution of this aberrant activity to Tat-induced cognitive decline will be determined. These
studies will relate changes in eCB signaling to network excitability in a model of HAND and link the aberrant
synaptic activity induced by Tat to cognitive decline.
Completion of these studies will identify a pathway induced by HIV Tat that unbalances eCB signaling. These
studies will provide a foundation to explore the clinical potential of drugs that normalize excitability to improve
cognitive function in HAND. Finally, the changes in eCB signaling that occur under neuroinflammatory
conditions could significantly alter the effects of exogenous cannabinoids on CNS function.
Status | Active |
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Effective start/end date | 3/15/92 → 2/28/25 |
Funding
- National Institute on Drug Abuse: $457,086.00
- National Institute on Drug Abuse: $380,000.00
- National Institute on Drug Abuse: $201,580.00
- National Institute on Drug Abuse: $380,000.00
- National Institute on Drug Abuse: $195,707.00
- National Institute on Drug Abuse: $207,627.00
- National Institute on Drug Abuse: $213,855.00
- National Institute on Drug Abuse: $459,312.00
- National Institute on Drug Abuse: $414,049.00
- National Institute on Drug Abuse: $376,200.00
- National Institute on Drug Abuse: $380,000.00
- National Institute on Drug Abuse: $167,766.00
- National Institute on Drug Abuse: $374,300.00
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