title: The impairment in spatial learning and hippocampal LTD induced through the PKA pathway in juvenile-onset diabetes rats are rescued by modulating NMDA receptor function.
abstract: Childhood- or early adulthood-onset type 1 diabetes is associated with modest impairments in cognition, and has an elevated risk of cognitive decline. Although an earlier onset age of diabetes has been identified as one of the strongest risk factors associated with cognitive dysfunction, little is known about the effects of cognitive performance associated with hippocampal function. Our previous study showed impaired working memory and hippocampal long-term depression (LTD) deficits in juvenile-onset diabetes mellitus (JDM) rats. Here, we demonstrated that treatment with the NMDA open-channel blocker, memantine, rescued hippocampal LTD and hippocampal-dependent memory in JDM rats. In addition, the impairment in LTD was attributed to a malfunction in NR2B-containing NMDA receptors. JDM rats exhibited excessive PKA activity, which may play a role in altered NMDA receptor function and impaired LTD. The changes in NR2B-containing NMDA receptors and PKA activity may be involved in learning impairments in JDM rats. Our findings suggest that NMDA open-channel blockers offer a potential strategy to treat cognitive deficits in childhood-onset diabetes.
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sacai
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Sachie
authors.initials: S
authors.lastname: Sasaki-Hamada
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan; Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8553, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Sugiyama
authors.affiliation: Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8553, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Saitoh
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mori
authors.affiliation: Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8553, Japan.
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan. Electronic address: okaji@rs.noda.tus.ac.jp.
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Oka
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D036881:Long-Term Synaptic Depression; D008297:Male; D008559:Memantine / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D065853:Spatial Learning / Q000187:drug effects / Q000502:physiology*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D017868:Cyclic AMP-Dependent Protein Kinases; D008559:Memantine
keywords: Diabetes; Learning; NMDA receptor; PKA; PKC; Synaptic plasticity