4-Aminopyridine improves spatial memory in a murine model of HIV-1 encephalitis.
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 (K(v)) 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 K(v) 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 K(v) channel dysfunction in disease but, more importantly, provide a potential target for adjunctive therapies for HAND.
Keblesh
James P
JP
Neurophysiology Laboratory, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
Dou
Huanyu
H
Gendelman
Howard E
HE
Xiong
Huangui
H
D015761:4-Aminopyridine / Q000494:pharmacology*; D015526:AIDS Dementia Complex / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology* / Q000821:virology; D000818:Animals; D001921:Brain / Q000473:pathology; D002469:Cell Separation; D015497:HIV-1; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007858:Learning / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D051379:Mice; D016513:Mice, SCID; D008854:Microscopy, Electron; D009000:Monocytes / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000502:physiology; D013028:Space Perception / Q000187:drug effects*; D013550:Swimming / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000502:physiology
D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D015761:4-Aminopyridine