title: Suppression of spreading depolarization and stabilization of dendritic spines by GLYX-13, an NMDA receptor glycine-site functional partial agonist.
abstract: Cortical spreading depolarization (SD) is a slow self-propagating wave of mass cellular depolarization in brain tissue, thought to be the underlying cause of migraine scintillating scotoma and aura, and associated with stroke, traumatic brain injury, and termination of status epilepticus. The N-methyl-d-aspartate subtype of glutamate receptor (NMDAR), which gates influx of calcium and is an important trigger of long-term synaptic plasticity, is also a contributor to the initiation and propagation of SD. The current study tested the potential of pharmacological modulation of NMDAR activity through the obligatory co-agonist binding site, to suppress the initiation of SD, and modulate the effects of SD on dendritic spine morphology, in in vitro hippocampal slices. A novel NMDAR functional glycine site partial agonist, GLYX-13, sometimes completely prevented the induction of SD and consistently slowed its rate of propagation. The passage of SD through the hippocampal CA1 region produced a rapid retraction of dendritic spines which reversed after neuronal depolarization had recovered. GLYX-13 improved the rate and extent of return of dendritic spines to their original sizes and locations following SD, suggesting that NMDAR modulators can protect synaptic connections in the brain from structural alterations elicited by SD. These data indicate that NMDAR modulation to renormalize activity may be an effective new treatment strategy for suppression or amelioration of the contribution of SD to short and long-term symptoms of migraine attacks, as well as the effects of SD on tissue damaged by stroke or traumatic brain injury.
authors.affiliation: Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY, USA.
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Zhang
authors.affiliation: Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.
authors.forename: C William
authors.initials: CW
authors.lastname: Shuttleworth
authors.affiliation: Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, McCormick School of Engineering and Applied Sciences, Northwestern University, Evanston, IL, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Moskal
authors.affiliation: Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY, USA; Department of Neurology, New York Medical College, Valhalla, NY, USA. Electronic address: patric_stanton@nymc.edu.
authors.forename: Patric K
authors.initials: PK
authors.lastname: Stanton
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D049229:Dendritic Spines / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D018684:Glycine Agents / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D008857:Microscopy, Interference; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D018684:Glycine Agents; D009842:Oligopeptides; C507283:GLYX-13 peptide; D011188:Potassium
keywords: CA1; Hippocampus; Migraine; Schaffer collateral; Spreading depression