Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons.
Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons.
复制标题
DOI：
10.1016/j.nbd.2016.06.008
复制
发表时间：
2016-10
影响因子：
6.1
通讯作者：
Hu XT
中科院分区：
文献类型：
--
作者：
Khodr CE;Chen L;Dave S;Al-Harthi L;Hu XT
人类免疫缺陷病毒1型（HIV-1）感染会导致神经和神经心理缺陷，这与内侧前额叶皮层（mPFC）和其他脆弱大脑区域的失调有关。我们评估了HIV感染对mPFC的影响以及靶向过度活跃的电压门控L型Ca 2+通道（L通道）和NMDA受体（NMDAR）的治疗潜力，如在HIV-1转基因（Tg）大鼠中建模的那样。采用全细胞膜片钳技术记录mPFC锥体神经元的膜特性和电压敏感性钙内流。与非Tg对照组大鼠相比，HIV-1 Tg大鼠的神经元表现出基强度降低、峰电位振幅和内向整流K+内流减少、动作电位数量增加以及异常放电趋势。神经元过度兴奋与异常增强的Ca 2+内流（独立于NMDAR）相关，后者可通过急性L通道阻滞消除。结合慢性封锁过度活跃的L-通道和NMDAR与开放通道阻滞剂废除艾滋病毒的影响尖峰，异常放电和Ca 2+电位半幅持续时间，但不是减少内向整流。相比之下，单独慢性阻断过度活跃的L-通道或NMDAR并不能缓解HIV诱导的mPFC过度兴奋性。这些研究表明，HIV改变mPFC神经元的活动失调膜兴奋性和Ca 2+流入通过L-通道。这使得这些神经元更容易受到兴奋性刺激的影响，并可能导致HIV相关的神经发病机制。过度活跃的L-通道/NMDAR的联合靶向治疗可缓解HIV诱导的mPFC锥体神经元功能障碍，强调了一种潜在的新治疗策略，可有效降低HIV诱导的mPFC中Ca 2+失调。
Human Immunodeficiency Virus type 1 (HIV-1) infection induces neurological and neuropsychological deficits, which are associated with dysregulation of the medial prefrontal cortex (mPFC) and other vulnerable brain regions. We evaluated the impact of HIV infection in the mPFC and the therapeutic potential of targeting over-active voltage-gated L-type Ca2+ channels (L-channel) and NMDA receptors (NMDAR), as modeled in HIV-1 transgenic (Tg) rats. Whole-cell patch-clamp recording was used to assess the membrane properties and voltage-sensitive Ca2+ potentials (Ca2+ influx) in mPFC pyramidal neurons. Neurons from HIV-1 Tg rats displayed reduced rheobase, spike amplitude and inwardly-rectifying K+ influx, increased numbers of action potentials, and a trend of aberrant firing compared to those from non-Tg control rats. Neuronal hyper-excitation was associated with abnormally-enhanced Ca2+ influx (independent of NMDAR), which was eliminated by acute L-channel blockade. Combined chronic blockade of over-active L-channels and NMDARs with open-channel blockers abolished HIV effects on spiking, aberrant firing and Ca2+ potential half-amplitude duration, though not the reduced inward rectification. In contrast, individual chronic blockade of over-active L-channels or NMDARs did not alleviate HIV-induced mPFC hyper-excitability. These studies demonstrate that HIV alters mPFC neuronal activity by dysregulating membrane excitability and Ca2+ influx through the L-channels. This renders these neurons more susceptible and vulnerable to excitatory stimuli, and could contribute to HIV-associated neuropathogenesis. Combined targeting of over-active L-channels/NMDARs alleviates HIV-induced dysfunction of mPFC pyramidal neurons, emphasizing a potential novel therapeutic strategy that may effectively decrease HIV-induced Ca2+ dysregulation in the mPFC.