Cell Biology: Research & TherapyISSN: 2324-9293

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HIV-induced hyperactivity of striatal neurons is associated with dysfunction of voltage-gated calcium and potassium channels in 12-month-old rats

Objectives: Despite combination antiretroviral therapy, HIV-associated neurocognitive disorders occur in ~50% of people living with HIV, which are associated with dysfunction of the corticostriatal pathway. The mechanism by which HIV alters the neuronal activity in the striatum is unknown. The goal of this study is to reveal dysfunction of striatal neurons in the context of neuroHIV during aging.

Methods: Using patch-clamping electrophysiology, we evaluated the activity of medium spiny neurons (MSNs), including firing, Ca2+ spikes mediated by voltage-gated Ca2+ channels (VGCCs), and K+ channel-mediated membrane excitability, in brain slices containing the dorsal striatum (a.k.a. the caudate-putamen) from 12-month-old HIV-1 transgenic (Tg) rats. We also assessed the protein expression of voltage-gated Cav1.2/Cav1.3 L-type Ca2+ channels (L-channels), NMDA receptors (NMDAR, NR2B subunit), and GABAA receptors (GABAARs, β2,3 subunit) in the striatum.

Results: We found that MSNs had significantly increased firing in 12-month-old (12m) Tg rats compared to age-matched non-Tg control rats. Unexpectedly, Ca2+ spikes were significantly reduced, while Kv channel activity was increased, in MSNs of Tg rats compared to non-Tg controls. The reduced Ca2+ spikes were associated with an abnormally increased expression of a shorter, less functional Cav1.2 L-channel form, while there was no significant change in the expression of NR2Bs or GABAARs.

Conclusion: Collectively, these novel findings initially reveal HIV-induced dysfunction of striatal MSNs in 12m-old rats, which is uncoupled from VGCC upregulation and reduced Kv activity (that we observed previously in younger HIV-1 Tg rats). Notably, such striatal dysfunction is also associated with HIV-induced hyperactivity/neurotoxicity of glutamatergic pyramidal neurons in the medial prefrontal cortex that send excitatory input to the striatum (demonstrated in our previous studies). Whether such MSN dysfunction is mediated by alterations in the functional activity instead of the expression of NR2b/GABAAR (or other subtypes) requires further investigation.

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