細胞生物学: 研究と治療

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

Christina E. Khodr*, Lihua Chen*, Lena Al-Harthi, Xiu-Ti Hu

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 Ca_v1.2/Ca_v1.3 L-type Ca²⁺ channels (L-channels), NMDA receptors (NMDAR, NR2B subunit), and GABA_A receptors (GABA_ARs, β_2,3 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 K_v 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 Ca_v1.2 L-channel form, while there was no significant change in the expression of NR2Bs or GABA_ARs.

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 K_v 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/GABA_AR (or other subtypes) requires further investigation.