4-aminopyridine improves spatial memory in a murine model of HIV-1 encephalitis

James P. Keblesh, Huanyu Dou, Howard Eliot Gendelman, Huangui Xiong

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)317-327
Number of pages11
JournalJournal of Neuroimmune Pharmacology
Volume4
Issue number3
DOIs
StatePublished - Sep 1 2009

Fingerprint

4-Aminopyridine
Encephalitis
HIV-1
SCID Mice
Long-Term Potentiation
Learning
Channelopathies
Voltage-Gated Potassium Channels
Water
Electrophysiology
Highly Active Antiretroviral Therapy
Microglia
Viral Proteins
Neuroglia
Spatial Memory
Hippocampus
Central Nervous System
Macrophages
Morbidity
Neurons

Keywords

  • 4-aminopyridine
  • EPSP
  • HIV-1 encephalitis
  • Hippocampal slice
  • Learning and memory
  • Voltage-gated K channels

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

Cite this

4-aminopyridine improves spatial memory in a murine model of HIV-1 encephalitis. / Keblesh, James P.; Dou, Huanyu; Gendelman, Howard Eliot; Xiong, Huangui.

In: Journal of Neuroimmune Pharmacology, Vol. 4, No. 3, 01.09.2009, p. 317-327.

Research output: Contribution to journalArticle

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