Perineuronal proteolysis and circuit dysfunction in HAND

由于强烈的兴奋性输入、可靠的GABA释放和快速放电，小清蛋白表达（PV） 神经元被认为代表同步网络事件的关键起搏器。PV神经元也 代表被神经元周网包裹的主要GABA能神经元群 (PNN)细胞外基质是一种晶格状的细胞外基质，被认为定位于神经元能输入。PNN中断 与PV兴奋性降低有关。重要的是，PV兴奋性缺陷影响 同步网络事件对注意力和长期记忆巩固至关重要。支持 最近的研究表明，减少海马PV细胞的多巴胺能输入， PV选择性谷氨酸受体的敲除或突触前谷氨酸能神经支配的减少， 与尖波涟漪（SWR）密度增加和长期记忆巩固缺陷有关。 PNN加工通过特定蛋白酶的作用发生。虽然金属蛋白酶的“a 具有血小板反应蛋白基序的去整合素和金属蛋白酶（ADAMTS）和分泌性基质 金属蛋白酶（MMP）家族成员可以切割特定的PNN组分，后者可以是 在人类免疫缺陷病毒（HIV）感染的背景下尤其重要。可溶性MMPs 由神经元和小胶质细胞表达，并且已知消化PNN组分，包括聚集蛋白聚糖和 短蛋白聚糖此外，虽然在猿猴的星形胶质细胞中没有检测到ADAMTS蛋白表达， 免疫缺陷病毒（SIV）模型中，PNN降解MMPs由星形胶质细胞高度表达， 大脑中有许多细胞类型。此外，在小鼠脑损伤模型中，选择性MMP抑制 减少PNN重塑。 先前已经证明，人HIV编码的达特蛋白可以增加人HIV感染的细胞增殖。 MMP-9是PNN加工的有效调节剂。达特蛋白是 在接受联合抗逆转录病毒治疗（cART）的个体的脑脊液中可检测到。在 本文包括的新的初步数据，我们表明，达特显着增加MMP-13的释放， 星形胶质细胞此外，我们在病毒学抑制的脑组织裂解物中观察到MMP-13的活性形式， 艾滋病毒感染者。在初步研究中，MMP-13可以有效地切割PNN组分。 已发表的工作将MMP-13表达与HIV感染联系起来，并且还显示PNN减少 HIV相关认知功能障碍（HAND）的背景。然而，重要的是， 和潜在的关键神经生理后果PNN中断的设置手还没有 被好好检查过了。在本申请中，我们计划检验HIV相关刺激物 包括达特在内的药物可以在体外和体内刺激MMP依赖的PNN加工， 对海马PV活动、神经元群体动力学和记忆巩固的影响。!

Due to strong excitatory input, reliable GABA release and fast firing, parvalbumin expressing (PV) neurons are thought to represent critical pacemakers for synchronous network events. PV neurons also represent the predominant GABAergic neuronal population that is enveloped by the perineuronal net (PNN), a lattice like extracellular matrix that is thought to localize glutamatergic input. Disruption of the PNN has been linked to reductions in PV excitability. Importantly, deficits in PV excitability influence synchronous network events critical to both attention and long-term memory consolidation. In support of this, recent studies have demonstrated that reduced glutamatergic input to hippocampal PV cells, through knockout of PV selective glutamate receptors or a reduction in presynaptic glutamatergic innervation, is linked to increases in sharp wave ripple (SWR) density and deficits in long term memory consolidation. PNN processing occurs through the actions of specific proteases. While metalloproteinases of the “a disintegrin and metalloproteinase with thrombospondin motifs” (ADAMTS) and secreted matrix metalloproteinase (MMP) family members can cleave specific PNN components, the latter may be particularly important in the background of human immunodeficiency virus (HIV) infection. Soluble MMPs are expressed by neurons and microglia and known to digest PNN components including aggrecan and brevican. In addition, while ADAMTS protein expression is not detected in astrocytes in a simian immunodeficiency virus (SIV) model, PNN degrading MMPs are highly expressed by astrocytes, the most numerous cell type in the brain. Moreover, in murine models of brain injury, selective MMP inhibition reduces PNN remodeling. It has previously been demonstrated that human HIV encoded Tat protein can increase the expression and/or cellular release of MMP-9, a potent modulator of PNN processing. Tat protein is detectable in the cerebrospinal fluid of individuals receiving combination anti-retroviral treatment (cART). In new preliminary data included herein, we show that Tat significantly increases release of MMP-13 from astrocytes. Moreover, we see active forms of MMP-13 in brain tissue lysates from virologically suppressed HIV-infected individuals. In preliminary studies, MMP-13 can efficiently cleaves PNN components. Published work has linked MMP-13 expression to HIV infection, and also shown reduced PNN integrity in the background HIV associated cognitive dysfunction (HAND). Importantly, however, causes and potentially critical neurophysiological consequences of PNN disruption in the setting of HAND have not been well examined. In the present application, we plan to test the hypothesis that HIV relevant stimuli including Tat can stimulate MMP-dependent PNN processing in vitro and in vivo, with consequent effects on hippocampal PV activity, neuronal population dynamics and memory consolidation. !