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4-Aminopyridine Improves Spatial Memory in a Murine Model of HIV-1 Encephalitis

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Abstract

HIV-1-associated neurocognitive disorders (HAND) remains a significant source of morbidity in the era of wide spread use of highly active antiretroviral therapy. Disease is precipitated by low levels of viral growth and glial immune activation within the central nervous system. Blood borne macrophage and microglia affect a proinflammatory response and release viral proteins that affects neuronal viability and leads to death of nerve cells. Increasing evidence supports the notion that HAND is functional channelopathy, but proof of this concept remains incomplete. Based on their role in learning and memory processes, we now posit that voltage-gated potassium (Kv) channels could be a functional substrate for disease. This was tested in the severe combined immunodeficient (SCID) mouse model of HIV-1 encephalitis (HIVE) by examining whether the Kv channel blocker, 4-aminopyridine (4-AP), could affect behavioral, electrophysiological, and morphological measures of learning and memory. HIVE SCID mice showed impaired spatial memory in radial arm water maze tests. Electrophysiology studies revealed a reduction of long-term potentiation (LTP) in the CA1 region of the hippocampus. Importantly, systemic administration of 4-AP blocked HIV-1-associated reduction of LTP and improved animal performance in the radial arm water maze. These results support the importance of Kv channel dysfunction in disease but, more importantly, provide a potential target for adjunctive therapies for HAND.

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Acknowledgments

The authors thank Mr. Tom Bargar and Dr. Jorge F. Rodriquez-Sierra for their assistance in electron microscopic studies. The authors extend a special thanks to Ms. Julie Ditter and Ms. Robin Taylor for their excellent administrative support. This work was supported by NIH grants R01 2NS041862.

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Authors and Affiliations

  1. Neurophysiology Laboratory, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA

    James P. Keblesh & Huangui Xiong

  2. Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA

    James P. Keblesh, Huanyu Dou, Howard E. Gendelman & Huangui Xiong

  3. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA

    James P. Keblesh, Huanyu Dou, Howard E. Gendelman & Huangui Xiong

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  1. James P. Keblesh
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  2. Huanyu Dou
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  3. Howard E. Gendelman
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  4. Huangui Xiong
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Correspondence to Huangui Xiong.

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Grant support: NIH NINDS 2R01 NS04862.

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Keblesh, J.P., Dou, H., Gendelman, H.E. et al. 4-Aminopyridine Improves Spatial Memory in a Murine Model of HIV-1 Encephalitis. J Neuroimmune Pharmacol 4, 317–327 (2009). https://doi.org/10.1007/s11481-009-9161-7

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