title: Neonatal NMDA receptor blockade disrupts spike timing and glutamatergic synapses in fast spiking interneurons in a NMDA receptor hypofunction model of schizophrenia.
abstract: The dysfunction of parvalbumin-positive, fast-spiking interneurons (FSI) is considered a primary contributor to the pathophysiology of schizophrenia (SZ), but deficits in FSI physiology have not been explicitly characterized. We show for the first time, that a widely-employed model of schizophrenia minimizes first spike latency and increases GluN2B-mediated current in neocortical FSIs. The reduction in FSI first-spike latency coincides with reduced expression of the Kv1.1 potassium channel subunit which provides a biophysical explanation for the abnormal spiking behavior. Similarly, the increase in NMDA current coincides with enhanced expression of the GluN2B NMDA receptor subunit, specifically in FSIs. In this study mice were treated with the NMDA receptor antagonist, MK-801, during the first week of life. During adolescence, we detected reduced spike latency and increased GluN2B-mediated NMDA current in FSIs, which suggests transient disruption of NMDA signaling during neonatal development exerts lasting changes in the cellular and synaptic physiology of neocortical FSIs. Overall, we propose these physiological disturbances represent a general impairment to the physiological maturation of FSIs which may contribute to schizophrenia-like behaviors produced by this model.
authors.affiliation: Biology Department, Howard University, Washington, DC, United States of America; Center for Neuroscience Research, Children's National Medical Center, Washington, DC, United States of America.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Jones
authors.affiliation: Center for Neuroscience Research, Children's National Medical Center, Washington, DC, United States of America.
authors.forename: Joshua G
authors.initials: JG
authors.lastname: Corbin
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, and Department of Pediatrics, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States of America.
authors.forename: Molly M
authors.initials: MM
authors.lastname: Huntsman
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000831:Animals, Newborn; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000009:adverse effects*; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D018698:Glutamic Acid / Q000378:metabolism; D007279:Injections, Subcutaneous; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051662:Kv1.1 Potassium Channel / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D001426:Bacterial Proteins; D018691:Excitatory Amino Acid Antagonists; D008164:Luminescent Proteins; C121001:NR2B NMDA receptor; D010320:Parvalbumins; D016194:Receptors, N-Methyl-D-Aspartate; C054562:yellow fluorescent protein, Bacteria; D051662:Kv1.1 Potassium Channel; D018698:Glutamic Acid; D016291:Dizocilpine Maleate