Journal of Neuroimmune Pharmacology

, Volume 4, Issue 3, pp 317–327 | Cite as

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

  • James P. Keblesh
  • Huanyu Dou
  • Howard E. Gendelman
  • Huangui Xiong
Original Article


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.


voltage-gated K+ channels 4-aminopyridine hippocampal slice EPSP learning and memory HIV-1 encephalitis 



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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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • James P. Keblesh
    • 1
    • 2
    • 3
  • Huanyu Dou
    • 2
    • 3
  • Howard E. Gendelman
    • 2
    • 3
  • Huangui Xiong
    • 1
    • 2
    • 3
  1. 1.Neurophysiology LaboratoryUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Center for Neurovirology and Neurodegenerative DisordersUniversity of Nebraska Medical CenterOmahaUSA
  3. 3.Department of Pharmacology and Experimental NeuroscienceUniversity of Nebraska Medical CenterOmahaUSA

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