title: Aldehyde dehydrogenase 2 deficiency increases resting-state glutamate and expression of the GluN1 subunit of N-methyl-D-aspartate receptor in the frontal cortex of mice.
abstract: Our previous study showed that Aldh2-knockout (Aldh2-KO) mice, an animal model of inactive aldehyde dehydrogenase 2 (ALDH2), have better spatial memory when compared with wild-type (WT) mice. Given that the neurotransmitter glutamate has been associated with learning and memory, the goal of the present study was to investigate whether the strain-dependent difference in spatial memory was associated with changes in glutamate transmitter levels or receptor function in the frontal cortex of Aldh2-KO and WT mice. Thus, we first measured extracellular glutamate levels in free-moving mice using microdialysis. Second, we studied protein expression of the N-methyl-D-aspartate (NMDA) receptor (GluN1) subunit and the α-amino-3-hydroxy-5 methylisoxazole-4-propionic acid (AMPA) receptor (GluA1) subunit in lipid raft fractions using Western blot (WB). The samples were collected for WB, and lipid rafts were prepared from the insoluble fraction of homogenate tissue. Protein concentration was measured in the whole cell lysate (WCL) and in five separate lipid raft fractions. Cholesterol was also measured in all fractions 1-5. The microdialysis study revealed that basal glutamate concentration in the dialysates was approximately three-fold (0.27 ± 0.12 μM) higher in Aldh2-KO mice than in WT (0.10 ± 0.03 μM) mice. We also found an increase in the expression of GluN1 in Aldh2-KO mice compared with WT mice, both in the WCL and fraction 5, but GluA1 levels were unchanged as measured by WB. Our novel findings provide the first evidence for the role of ALDH2 in glutamate release and GluN1 protein expression in the frontal cortex. The observed strain differences in glutamate levels and GluN1 expression may suggest that enhanced glutamatergic function facilitates improved spatial memory in Aldh2-KO mice and such observation deserves further investigation.
authors.affiliation: Department of Forensic Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793, Japan. Electronic address: jamal@kms.ac.jp.
authors.forename: Mostofa
authors.initials: M
authors.lastname: Jamal
authors.affiliation: Department of Anesthesiology and Emergency Medicine, Faculty of Medicine, Kagawa University, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Ono
authors.affiliation: Department of Forensic Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ameno
authors.affiliation: Department of Anesthesiology and Emergency Medicine, Faculty of Medicine, Kagawa University, Japan.
authors.forename: Gotaro
authors.initials: G
authors.lastname: Shirakami
authors.affiliation: Department of Forensic Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Department of Forensic Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Takakura
authors.affiliation: Department of Forensic Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kinoshita
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000172:deficiency*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D004195:Disease Models, Animal; D005625:Frontal Lobe / Q000378:metabolism*; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D065852:Spatial Memory / Q000502:physiology*
chemical_list: D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D018698:Glutamic Acid; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C121673:Gprin1 protein, mouse; C515029:ALDH2 protein, mouse
keywords: AMPA receptor GluA1 subunit; Aldh2-KO mice; Frontal cortex; Glutamate; In vivo microdialysis; NMDA receptor GluN1 subunit