Persistent negative and cognitive symptoms are a primary cause of chronic disability and poor long-term outcome in schizophrenia. Deficits involve sensory-level disturbances, as well as abnormalities of higher level cognition. Phencyclidine (PCP) and other antagonists of N-methyl-D-aspartate (NMDA)-mediated neurotransmission induce symptoms and cognitive deficits that closely resemble those of schizophrenia and incorporate sensory, as well as higher cognitive changes, indicating a potentially critical role of NMDA receptors in the etiopathology of negative symptoms and cognitive dysfunction. NMDA receptors are modulated in vivo by glycine and D-serine, which bind to the glycine modulatory site (GMS) of the NMDA receptor complex. Clinical trials with GMS agonists have yielded highly encouraging clinical data with regard to negative symptoms, although effects on neurocognition remain to be determined. The present project will investigate effects of D-serine on neurocognitive deficits associated with schizophrenia, using both eventrelated potential (ERP) and behavioral measures sensitive to bottom-up effects of early cortical dysfunction. The project consists of two components. First, neurocognitive measures will be added to a recently funded study of D-serine treatment in both chronic and prodromal subjects in order to evaluate the degree to which GMS agonist treatment can reverse or prevent neurocognitive deficits associated with schizophrenia. Second, parallel studies in transgenic mouse models will evaluate the degree to which ERP deficits in schizophrenia can be reproduced by genetic manipulations aimed at the NMDA GMS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH060450-10
Application #
7858390
Study Section
Special Emphasis Panel (ZMH1)
Project Start
Project End
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
10
Fiscal Year
2009
Total Cost
$235,721
Indirect Cost
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
Dickie, Erin W; Ameis, Stephanie H; Shahab, Saba et al. (2018) Personalized Intrinsic Network Topography Mapping and Functional Connectivity Deficits in Autism Spectrum Disorder. Biol Psychiatry 84:278-286
Di Martino, Adriana; O'Connor, David; Chen, Bosi et al. (2017) Enhancing studies of the connectome in autism using the autism brain imaging data exchange II. Sci Data 4:170010
Wolosker, Herman; Balu, Darrick T; Coyle, Joseph T (2016) The Rise and Fall of the d-Serine-Mediated Gliotransmission Hypothesis. Trends Neurosci 39:712-721
Balu, Darrick T; Li, Yan; Takagi, Shunsuke et al. (2016) An mGlu5-Positive Allosteric Modulator Rescues the Neuroplasticity Deficits in a Genetic Model of NMDA Receptor Hypofunction in Schizophrenia. Neuropsychopharmacology 41:2052-61
Coyle, Joseph T; Balu, Darrick T; Puhl, Matthew D et al. (2016) History of the Concept of Disconnectivity in Schizophrenia. Harv Rev Psychiatry 24:80-6
Valk, Sofie L; Di Martino, Adriana; Milham, Michael P et al. (2015) Multicenter mapping of structural network alterations in autism. Hum Brain Mapp 36:2364-73
Ishiwata, Sayuri; Umino, Asami; Balu, Darrick T et al. (2015) Neuronal serine racemase regulates extracellular D-serine levels in the adult mouse hippocampus. J Neural Transm (Vienna) 122:1099-103
Vinette, Sarah A; Bray, Signe (2015) Variation in functional connectivity along anterior-to-posterior intraparietal sulcus, and relationship with age across late childhood and adolescence. Dev Cogn Neurosci 13:32-42
Balu, Darrick T; Coyle, Joseph T (2015) The NMDA receptor 'glycine modulatory site' in schizophrenia: D-serine, glycine, and beyond. Curr Opin Pharmacol 20:109-15
Takagi, Shunsuke; Balu, Darrick T; Coyle, Joseph T (2015) Subchronic pharmacological and chronic genetic NMDA receptor hypofunction differentially regulate the Akt signaling pathway and Arc expression in juvenile and adult mice. Schizophr Res 162:216-21

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