HIV-1 Tat causes cognitive deficits and selective loss of parvalbumin, somatostatin, and neuronal nitric oxide synthase expressing hippocampal CA1 interneuron subpopulations

Abstract

Memory deficits are characteristic of HIV-associated neurocognitive disorders (HAND) and co-occur with hippocampal pathology. The HIV-1 transactivator of transcription (Tat), a regulatory protein, plays a significant role in these events, but the cellular mechanisms involved are poorly understood. Within the hippocampus, diverse populations of interneurons form complex networks; even subtle disruptions can drastically alter synaptic output, resulting in behavioral dysfunction. We hypothesized that HIV-1 Tat would impair cognitive behavior and injure specific hippocampal interneuron subtypes. Male transgenic mice that inducibly expressed HIV-1 Tat (or non-expressing controls) were assessed for cognitive behavior or had hippocampal CA1 subregions evaluated via interneuron subpopulation markers. Tat exposure decreased spatial memory in a Barnes maze and mnemonic performance in a novel object recognition test. Tat reduced the percentage of neurons expressing neuronal nitric oxide synthase (nNOS) without neuropeptide Y immunoreactivity in the stratum pyramidale and the stratum radiatum, parvalbumin in the stratum pyramidale, and somatostatin in the stratum oriens, which are consistent with reductions in interneuron-specific interneuron type 3 (IS3), bistratified, and oriens-lacunosum-moleculare interneurons, respectively. The findings reveal that an interconnected ensemble of CA1 nNOS-expressing interneurons, the IS3 cells, as well as subpopulations of parvalbumin- and somatostatin-expressing interneurons are preferentially vulnerable to HIV-1 Tat. Importantly, the susceptible interneurons form a microcircuit thought to be involved in feedback inhibition of CA1 pyramidal cells and gating of CA1 pyramidal cell inputs. The identification of vulnerable CA1 hippocampal interneurons may provide novel insight into the basic mechanisms underlying key functional and neurobehavioral deficits associated with HAND.

Effects of HIV and Methamphetamine on Brain and Behavior: Evidence from Human Studies and Animal Models

“…Overall, both models have shown several neuropathological features observed in human AIDS brains (e.g. synaptodendritic loss, astrogliosis, and microgliosis) and neurobehavioral disturbances (Carey et al 2012; Gorantla et al 2012; Fitting et al 2013; Marks et al 2016). The effects of cofactors in HIV infection such as Meth exposure can be investigated in these animal models.…”

Conditional Human Immunodeficiency Virus Transactivator of Transcription Protein Expression Induces Depression-like Effects and Oxidative Stress

“…Dox treatment induces Tat protein expression in these mice at concentrations of 0.1–0.9 ng/ml in vitro (48), comparable to cerebrospinal fluid Tat concentrations detected in antiretroviral therapy-treated HIV patients (12). Prior studies of Dox-induced Tat-expressing mice have reported cellular (48–55), brain structural (56), and behavioral or cognitive (14,49,50,52–55,57–60) abnormalities. However, to date, no studies have reported on whether controlled Tat protein expression induces depression-like behavior on tasks commonly used to assess such behavior in mice.…”

Parvalbumin and Neuropeptide Y Neuronal Loss in the Hippocampal CA1 Subarea is Associated with Cognitive Deficits in a Rat Model of Chronic Cerebral Hypoperfusion

“…GABAergic cell loss in the hippocampus has been reported in animal models of AD, VaD, aging and epilepsy, all of which present cognitive impairments at different levels according to the previous research [9,22,25,35,40]. These findings indicate that there may be a causal relationship between these two factors.…”

“…However, the alteration of GABAergic interneurons in the hippocampus has not been clearly identified in CCH so far, even though other pathological changes including neuronal damage, glial activation and oxidative stress have been already reported [6,10,16]. Parvalbumin (PV, a calcium-binding protein)-, neuropeptide Y (NPY, a neuropeptide)-and somatostatin (SOM, another neuropeptide)-positive cells are three well-known subclasses of GABAergic interneurons [17,18] and tend to have an essential role in the modulation of cognitive ability [19][20][21][22]. PV-positive interneurons in CA1 of hippocampus are required for spatial working [19].…”