Perineuronal proteolysis and circuit dysfunction in HAND

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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. !