Khodr Christina E, Chen Lihua, Al-Harthi Lena, Hu Xiu-Ti
Department of Microbial Pathogens and Immunity, Rush University Medical Center, Cohn Research Building, Rm.610, 1735 W. Harrison Street, Chicago, IL 60612, USA.
Membranes (Basel). 2022 Jul 28;12(8):737. doi: 10.3390/membranes12080737.
Despite combination antiretroviral therapy, HIV-associated neurocognitive disorders (HAND) occur in ~50% of people living with HIV (PLWH), 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 the dysfunction of striatal neurons in the context of neuroHIV during aging. Using patch-clamping electrophysiology, we evaluated the functional activity of medium spiny neurons (MSNs), including firing, Ca spikes mediated by voltage-gated Ca 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 (12mo) HIV-1 transgenic (HIV-1 Tg) rats. We also assessed the protein expression of voltage-gated Ca1.2/Ca1.3 L-type Ca channels (L-channels), NMDA receptors (NMDAR, NR2B subunit), and GABA receptors (GABARs, β subunit) in the striatum. We found that MSNs had significantly increased firing in 12mo HIV-1 Tg rats compared to age-matched non-Tg control rats. Unexpectedly, Ca spikes were significantly reduced, while K channel activity was increased, in MSNs of HIV-1 Tg rats compared to non-Tg ones. The reduced Ca spikes were associated with an abnormally increased expression of a shorter, less functional Ca1.2 L-channel form, while there was no significant change in the expression of NR2Bs or GABARs. Collectively, the present study initially reveals neuroHIV-induced dysfunction of striatal MSNs in 12mo-old (middle) rats, which is uncoupled from VGCC upregulation and reduced K activity (that we previously identified 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 (mPFC) 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/GABAR (or other subtypes) requires further investigation.
尽管采用了联合抗逆转录病毒疗法，但约50%的HIV感染者（PLWH）仍会出现与HIV相关的神经认知障碍（HAND），这与皮质纹状体通路功能障碍有关。HIV改变纹状体神经元活动的机制尚不清楚。本研究的目的是揭示衰老过程中神经HIV背景下纹状体神经元的功能障碍。我们使用膜片钳电生理学方法，评估了来自12月龄（12mo）HIV-1转基因（HIV-1 Tg）大鼠的包含背侧纹状体（又称尾状核-壳核）的脑片中中等棘状神经元（MSN）的功能活动，包括放电、电压门控钙通道（VGCC）介导的钙峰以及钾通道介导的膜兴奋性。我们还评估了纹状体中电压门控Ca1.2/Ca1.3 L型钙通道（L通道）、NMDA受体（NMDAR，NR2B亚基）和GABA受体（GABARs，β亚基）的蛋白表达。我们发现，与年龄匹配的非Tg对照大鼠相比，12mo HIV-1 Tg大鼠的MSN放电显著增加。出乎意料的是，与非Tg大鼠相比，HIV-1 Tg大鼠的MSN中钙峰显著减少，而钾通道活性增加。钙峰减少与功能较弱的较短形式Ca1.2 L通道的异常表达增加有关，而NR2B或GABARs的表达没有显著变化。总体而言，本研究初步揭示了神经HIV在12月龄（中年）大鼠中诱导的纹状体MSN功能障碍，这与VGCC上调和钾活性降低（我们之前在年轻HIV-1 Tg大鼠中发现）无关。值得注意的是，这种纹状体功能障碍还与HIV诱导的内侧前额叶皮质（mPFC）中谷氨酸能锥体神经元的多动/神经毒性有关，这些神经元向纹状体发送兴奋性输入（我们之前的研究已证明）。这种MSN功能障碍是否由功能活动而非NR2b/GABAR（或其他亚型）的表达改变介导，需要进一步研究。
