# Chloride channel-dependent mechanisms of opiate and HIV-induced synaptodendritic injury

> **NIH NIH R21** · VIRGINIA COMMONWEALTH UNIVERSITY · 2022 · $194,063

## Abstract

Opioid use disorder (OUD) in people infected with HIV-1 (PWH) exacerbates the pathobiology of neuroHIV and
HIV-associated neurocognitive disorder (HAND) via complex mechanisms involving direct peripheral (e.g.,
immune suppression) and CNS (e.g., neuroinflammation, blood-brain barrier damage, and neuronal injury)
effects. Although glutamatergic excitotoxicity remains the major driving force in HIV-dependent neuronal injury,
emerging evidence from our lab indicates that the loss of inhibitory GABAergic control and [Cl−]i homeostasis
not only contributes to a loss of inhibition, but also increases the excitatory/neurotoxic effects of glutamate at
NMDA and AMPA receptors. This proposal directly tests the assumption that [Cl−]i-dependent net losses of
neuronal inhibition will increase excitation and promote excitotoxic. In mature neurons, intracellular Cl−
concentration ([Cl−]i) is dynamically regulated by membrane ion channels (GABAA and glycine receptors) and
Cl− channels and transporters. By controlling [Cl−]i, these channels and transporters regulate the Cl−
equilibrium potential (ECl) and neuronal inhibition and we have already shown the KCC2 loss-of-function in
OUD/neuroHIV models leads to [Cl−]i increases, elevated ECl, and excitotoxicity. We discovered a previously
unidentified a ClC-1-like voltage-dependent Cl− channel that differentially regulates the excitability of dopamine
receptor D1- and D2- expressing (D1 and D2, respectively) striatal medium spiny neurons (MSNs) and is
disrupted by opioids and HIV Tat. We hypothesize that opioids and HIV-1 disrupt [Cl−]i, homeostasis via a
voltage-gated ClC Cl− channel resulting in synaptodendritic injury. This hypothesis will be tested in the
following specific aims and if confirmed will be a conceptual shift in our understanding of how opioids and HIV
contribute to excitotoxicity. Aim 1 will identify the mechanisms by which opioids and HIV dysregulate voltage-
dependent ClC-1 channels and Cl− homeostasis in vitro. Our preliminary findings suggest that ClC-1
significantly affects voltage-dependent Cl− currents in D1 and D2 MSNs. The extent to which ClC-1 mediates
the HIV and opioid-induced pathology will be explored using gain-of-function, loss-of-function strategies, and
confirmed in vitro and in vivo/ex vivo using electrophysiologic, pharmacologic, and genetic approaches at the
cell and molecular levels. Aim 2. Establish to what extent ClC-1 modulation contributes to the synaptodendritic
injury caused by opioids and HIV-induced dysregulation of Cl− homeostasis. We predict that the dysregulation
of [Cl−]i homeostasis amplifies synaptodendritic injury in MSNs in OUD/neuroHIV models. Since ClC-1 can be a
novel source of activity-dependent Cl− entry, we also predict that opioids and HIV Tat cause neuronal injury via
a complex mechanism involving ClC-1 modulation and, thus, synaptic disinhibition. This project will test
whether opioids and HIV dysregulate [Cl−]i homeostasis and cause neuronal injury via...

## Key facts

- **NIH application ID:** 10548312
- **Project number:** 1R21DA057153-01
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Kurt F Hauser
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $194,063
- **Award type:** 1
- **Project period:** 2022-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10548312

## Citation

> US National Institutes of Health, RePORTER application 10548312, Chloride channel-dependent mechanisms of opiate and HIV-induced synaptodendritic injury (1R21DA057153-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10548312. Licensed CC0.

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