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

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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.

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Acknowledgments

This work was supported by grants K99 DA033878 (SF), K99 DA039791 (JJP), F32 DA039039 (CJS), T32 DA007027 (WDM and CJS), R01 DA018633 (KFH), R01 DA024461 (PEK), R01 DA034231 (PEK and KFH), R01 DA033200 (KFH), R01 MH094626 (ARM), R21 MH103695 (ARM), and K02 DA027374 (KFH) from the National Institute on Drug Abuse. The authors thank Dr. Marie Bonhomme for the assistance with the immunohistochemical analysis, Mr. Phu Vo for the help in maintaining the mice, Ms. Yun Ji for laboratory support, and Dr. Thomas Reeves for proofreading the manuscript.

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Authors and Affiliations

  1. Department of Pharmacology & Toxicology, Virginia Commonwealth University School of Medicine, Kontos Medical Sciences Building, 1217 East Marshall Street, Richmond, VA, 23298-0613, USA

    William D. Marks, Jason J. Paris, Christina J. Schier, Melissa D. Denton, Pamela E. Knapp & Kurt F. Hauser

  2. Department of Psychology & Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-3270, USA

    Sylvia Fitting

  3. Department of Anatomy & Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298-0709, USA

    A. Rory McQuiston, Pamela E. Knapp & Kurt F. Hauser

  4. Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, 23298-0059, USA

    Pamela E. Knapp & Kurt F. Hauser

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  1. William D. Marks
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Correspondence to Kurt F. Hauser.

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Animal procedures were approved by the Virginia Commonwealth University Institutional Animal Care and Use Committee and are in accordance with Association for Assessment and Accreditation of Laboratory Animal Care guidelines.

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Marks, W.D., Paris, J.J., Schier, C.J. et al. HIV-1 Tat causes cognitive deficits and selective loss of parvalbumin, somatostatin, and neuronal nitric oxide synthase expressing hippocampal CA1 interneuron subpopulations. J. Neurovirol. 22, 747–762 (2016). https://doi.org/10.1007/s13365-016-0447-2

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