title: NAAG Peptidase Inhibitors Act via mGluR3: Animal Models of Memory, Alzheimer's, and Ethanol Intoxication.
abstract: Glutamate carboxypeptidase II (GCPII) inactivates the peptide neurotransmitter N-acetylaspartylglutamate (NAAG) following synaptic release. Inhibitors of GCPII increase extracellular NAAG levels and are efficacious in animal models of clinical disorders via NAAG activation of a group II metabotropic glutamate receptor. mGluR2 and mGluR3 knock-out (ko) mice were used to test the hypothesis that mGluR3 mediates the activity of GCPII inhibitors ZJ43 and 2-PMPA in animal models of memory and memory loss. Short- (1.5 h) and long- (24 h) term novel object recognition tests were used to assess memory. Treatment with ZJ43 or 2-PMPA prior to acquisition trials increased long-term memory in mGluR2, but not mGluR3, ko mice. Nine month-old triple transgenic Alzheimer's disease model mice exhibited impaired short-term novel object recognition memory that was rescued by treatment with a NAAG peptidase inhibitor. NAAG peptidase inhibitors and the group II mGluR agonist, LY354740, reversed the short-term memory deficit induced by acute ethanol administration in wild type mice. 2-PMPA also moderated the effect of ethanol on short-term memory in mGluR2 ko mice but failed to do so in mGluR3 ko mice. LY354740 and ZJ43 blocked ethanol-induced motor activation. Both GCPII inhibitors and LY354740 also significantly moderated the loss of motor coordination induced by 2.1 g/kg ethanol treatment. These data support the conclusion that inhibitors of glutamate carboxypeptidase II are efficacious in object recognition models of normal memory and memory deficits via an mGluR3 mediated process, actions that could have widespread clinical applications.
authors.affiliation: Department of Biology, Georgetown University, 37th and O Sts., N.W., Washington, D.C., 20057-1225, USA.
authors.forename: Rafal T
authors.initials: RT
authors.lastname: Olszewski
authors.affiliation: Department of Biology, Georgetown University, 37th and O Sts., N.W., Washington, D.C., 20057-1225, USA.
authors.forename: Karolina J
authors.initials: KJ
authors.lastname: Janczura
authors.affiliation: Department of Biology, Georgetown University, 37th and O Sts., N.W., Washington, D.C., 20057-1225, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Bzdega
authors.affiliation: Department of Biology, Georgetown University, 37th and O Sts., N.W., Washington, D.C., 20057-1225, USA.
authors.forename: Elise K
authors.initials: EK
authors.lastname: Der
authors.affiliation: Department of Biology, Georgetown University, 37th and O Sts., N.W., Washington, D.C., 20057-1225, USA.
authors.forename: Faustino
authors.initials: F
authors.lastname: Venzor
authors.affiliation: Department of Biology, Georgetown University, 37th and O Sts., N.W., Washington, D.C., 20057-1225, USA.
authors.forename: Brennen
authors.initials: B
authors.lastname: O'Rourke
authors.affiliation: Department of Biology, Georgetown University, 37th and O Sts., N.W., Washington, D.C., 20057-1225, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hark
authors.affiliation: Department of Biology, Georgetown University, 37th and O Sts., N.W., Washington, D.C., 20057-1225, USA.
authors.forename: Kirsten E
authors.initials: KE
authors.lastname: Craddock
authors.affiliation: Department of Biology, Georgetown University, 37th and O Sts., N.W., Washington, D.C., 20057-1225, USA.
authors.forename: Shankar
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Department of Neuroscience, Georgetown University, Washington, D.C., 20057, USA.
authors.forename: Charbel
authors.initials: C
authors.lastname: Moussa
authors.affiliation: Department of Biology, Georgetown University, 37th and O Sts., N.W., Washington, D.C., 20057-1225, USA. nealej@georgetown.edu.
authors.forename: Joseph H
authors.identifier: http://orcid.org/0000-0002-6197-0807
authors.initials: JH
authors.lastname: Neale
mesh_terms: D000435:Alcoholic Intoxication / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000172:deficiency*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; C486211:ZJ43; C102718:metabotropic glutamate receptor 3; D000431:Ethanol; D014508:Urea; D043425:Glutamate Carboxypeptidase II
keywords: Alzheimer’s mice; Ethanol intoxication; GCPII; Glutamate carboxypeptidase II; Memory; N-Acetylaspartylglutamate; NAAG; mGluR3 knockout mice