title: 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.
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University School of Medicine, Kontos Medical Sciences Building, 1217 East Marshall Street, Richmond, VA, 23298-0613, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Marks
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University School of Medicine, Kontos Medical Sciences Building, 1217 East Marshall Street, Richmond, VA, 23298-0613, USA.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Paris
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University School of Medicine, Kontos Medical Sciences Building, 1217 East Marshall Street, Richmond, VA, 23298-0613, USA.
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Schier
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University School of Medicine, Kontos Medical Sciences Building, 1217 East Marshall Street, Richmond, VA, 23298-0613, USA.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Denton
authors.affiliation: Department of Psychology & Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-3270, USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Fitting
authors.affiliation: Department of Anatomy & Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298-0709, USA.
authors.forename: A Rory
authors.initials: AR
authors.lastname: McQuiston
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University School of Medicine, Kontos Medical Sciences Building, 1217 East Marshall Street, Richmond, VA, 23298-0613, USA.|Department of Anatomy & Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298-0709, USA.|Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, 23298-0059, USA.
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Knapp
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University School of Medicine, Kontos Medical Sciences Building, 1217 East Marshall Street, Richmond, VA, 23298-0613, USA. kurt.hauser@vcuhealth.org.|Department of Anatomy & Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298-0709, USA. kurt.hauser@vcuhealth.org.|Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, 23298-0059, USA. kurt.hauser@vcuhealth.org.
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism* / Q000503:physiopathology; D003071:Cognition / Q000502:physiology; D060825:Cognitive Dysfunction / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005786:Gene Expression Regulation; D007395:Interneurons / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency / Q000235:genetics*; D010320:Parvalbumins / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D013004:Somatostatin / Q000172:deficiency / Q000235:genetics*; D019076:Transgenes; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism
chemical_list: D009478:Neuropeptide Y; D010320:Parvalbumins; D054322:tat Gene Products, Human Immunodeficiency Virus; D013004:Somatostatin; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse
keywords: Bistratified cell; Interneuron specific interneuron type 3 (IS3); NeuroAIDS; Neurodegeneration; Oriens-lacunosum-moleculare cell (O-LM); Spatial memory