title: Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner.
abstract: NMDA receptors are key regulators of synaptic plasticity, and their hypofunction is thought to contribute to the pathophysiology of CNS disorders. Furthermore, NMDA receptors participate in the formation, maintenance, and elimination of synapses. The consequences of NMDA receptor hypofunction on synapse biology were explored in a genetic mouse model, in which the levels of NMDA receptors are reduced to 10% of normal levels (i.e., NR1-knockdown mice). In these mice, synapse number is reduced in an age-dependent manner; reductions are observed at the postpubertal age of 6 wk, but normal at 2 wk of age. Efforts to uncover the biochemical underpinnings of this phenomenon reveal synapse-specific reductions in 14-3-3ε protein and in Disrupted in Schizophrenia-1 (DISC1), two schizophrenia susceptibility factors that have been implicated in the regulation of spine density. Subchronic administration of MK-801, an NMDA receptor antagonist, produces similar synaptic reductions in both spine density and DISC1, indicating that synaptic levels of DISC1 are regulated by NMDA receptor function. The synaptic reduction of DISC1 and 14-3-3ε is developmentally correlated with the age-dependent decrease in striatal spine density.
authors: Department of Pharmacology and Toxicology, University of Toronto, ON, Canada M5S 1A8. a.ramsey@utoronto.ca
authors: Amy J
authors: AJ
authors: Ramsey
authors: Marija
authors: M
authors: Milenkovic
authors: Ana F
authors: AF
authors: Oliveira
authors: Yasmin
authors: Y
authors: Escobedo-Lozoya
authors: Saurav
authors: S
authors: Seshadri
authors: Ali
authors: A
authors: Salahpour
authors: Akira
authors: A
authors: Sawa
authors: Ryohei
authors: R
authors: Yasuda
authors: Marc G
authors: MG
authors: Caron
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D003342:Corpus Striatum / Q000166:cytology* / Q000502:physiology; D049229:Dendritic Spines / Q000378:metabolism / Q000502:physiology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D015180:Electrophoresis, Gel, Two-Dimensional; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D007150:Immunohistochemistry; D008124:Locomotion / Q000502:physiology; D051379:Mice; D008854:Microscopy, Electron; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012919:Social Behavior; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D048948:14-3-3 Proteins; C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate