title: The N-methyl-D-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats.
abstract: NMDA receptor (NMDAR) activity has been strongly implicated in both in vitro and in vivo learning models and the decline in cognitive function associated with aging and is linked to a decrease in NMDAR functional expression. GLYX-13 is a tetrapeptide (Thr-Pro-Pro-Thr) which acts as a NMDAR receptor partial agonist at the glycine site. GLYX-13 was administered to young adult (3 months old) and aged (27-32 months old) Fischer 344 X Brown Norway F1 rats (FBNF1), and behavioral learning tested in trace eye blink conditioning (tEBC), a movable platform version of the Morris water maze (MWM), and alternating t-maze tasks. GLYX-13 (1mg/kg, i.v.) enhanced learning in both young adult and aging animals for MWM and alternating t-maze, and increased tEBC in aging rats. We previously showed optimal enhancement of tEBC in young adult rats given GLYX-13 at the same dose. Of these learning tasks, the MWM showed the most robust age related deficit in learning. In the MWM, GLYX-13 enhancement of learning was greater in the old compared to the young adult animals. Examination of the induction of long-term potentiation (LTP) and depression (LTD) at Schaffer collateral-CA1 synapses in hippocampal slices showed that aged rats showed marked, selective impairment in the magnitude of LTP evoked by a sub-maximal tetanus, and that GLYX-13 significantly enhanced the magnitude of LTP in slices from both young adult and aged rats without affecting LTD. These data, combined with the observation that the GLYX-13 enhancement of learning was greater in old than in young adult animals, suggest that GLYX-13 may be a promising treatment for deficits in cognitive function associated with aging.
authors.affiliation: Department of Biomedical Engineering, The Falk Center for Molecular Therapeutics, Northwestern University, 1801 Maple Avenue, Evanston, IL 60201, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Burgdorf
authors.forename: Xiao-lei
authors.initials: XL
authors.lastname: Zhang
authors.forename: Craig
authors.initials: C
authors.lastname: Weiss
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Matthews
authors.forename: John F
authors.initials: JF
authors.lastname: Disterhoft
authors.forename: Patric K
authors.initials: PK
authors.lastname: Stanton
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Moskal
mesh_terms: D000375:Aging / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D003215:Conditioning, Eyelid / Q000187:drug effects; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: D009842:Oligopeptides; D016194:Receptors, N-Methyl-D-Aspartate; C507283:GLYX-13 peptide