Abstract
Cyclophilin D (Cyp D) is implicated in cell death pathway and blockade of Cyp D could be a potent therapeutic strategy for degenerative disorders such as Alzheimer's disease, ischemia, and multiple sclerosis, but physiological role of Cyp D remains elusive. Here, we investigated the ability of learning and memory in several behavioral tasks in mice that lacked Cyp D (Cyp D^−/−^) and the relationship between ability of learning and memory and hippocampal architecture or neuronal transmission in Cyp D^−/−^ mice. Cyp D^−/−^ mice showed impairments of short‐term memory in the Y‐maze, object recognition memory in the novel‐object recognition test, reference memory in the water maze test, and associative learning in the conditioned fear learning test. Hippocampal infusion of Cyclosporine A, which binds to Cyp D, replicated the defect in hippocampus‐dependent cognition observed in Cyp D^−/−^ mice. The Cyp D^−/−^ mice did not show histopathological abnormalities upon Nissl staining and GFAP immunostaining or irregular expression of neuronal and glial marker proteins on Western blotting. However, release of glutamate and acetylcholine was decreased from the hippocampus in response to high‐potassium treatment in the Cyp D^−/−^ mice than in the wild‐type mice. These results suggest a physiological role for Cyp D in learning and memory via the regulation of neurotransmission. © 2009 Wiley‐Liss, Inc.