The Center has focused on glutamatergic mechanisms, especially in the hippocampus, in experimental models to explore testable hypotheses about their involvement in the cognitive manifestations of schizophrenia. The over-arching hypothesis of the Center has been that hypofunction of a subpopulation of brain NMDA receptors contributes to the clinical features of schizophrenia. During the last 5 years, significant advances have been made that lend support to our hypotheses, including the development of animal models that more faithfully recreate the synaptic pathology of the disorder, the characterization of hippocampal memory processes in rodents, such as transitive inference, that are relevant to schizophrenia, and the identification of risk genes by others that affect glutamatergic neurotransmission. The Center consists of seven Projects and 3 Cores. Project 1: Benes has shown that amygdalar picrotoxin injection recreates in hippocampal CA2/3 neuropathologic changes similar to those in schizophrenia and will define the molecular and electrophysiologic consequences of this lesion. Project 2: Lisman will examine the interaction between dopamine and NMDA receptors in the hippocampus and their role in novelty detection, which is impaired in schizophrenia. Project 3: Eichenbaum will characterize the NMDA receptor's role in components of pragmatic memory known to be affected in schizophrenia. Project 4: Coyle has created mice with conditional knockouts of seririe racemase and glutamate carboxypeptidase II to determine the electrophysiologic and behavioral consequences of suppressing their expression jn young adulthood. Furthermore, they will examine the mechanisms of action of the protein encoded by G72, a risk gene in schizophrenia that reputedly enhances D-serine catabolism. Project 5: Yurgelun-Todd will use MRS to measure NAA and NAAG levels in the brains of schizophrenic subjects and animal models, and on BOLD signal changes in fMRI. Project 6: Goff will determine the efficacy of D-serine in schizophrenic patients receiving concurrent antipsychotics and will correlate treatment responses to relevant genotypes such as GCPII, G72 and GRM3. Project 7: Javitt will evaluate the effects of D-serine treatment on sensory processing measures and higher neurocognitive disturbances in prodromal and established schizophrenics. Computational Core: Hasselmo will develop computational models based on the findings of the Center. Biostatistical Core: Lange will provide statistical support for Center investigators. Administrative Core: Coyle will provide scientific oversight and budgetary administration to insure that the goals are achieved.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH060450-11
Application #
7858393
Study Section
Special Emphasis Panel (ZMH1-ERB-S (04))
Program Officer
Zalcman, Steven J
Project Start
2000-07-21
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
11
Fiscal Year
2010
Total Cost
$1,701,492
Indirect Cost
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
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
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
Alaerts, Kaat; Nayar, Kritika; Kelly, Clare et al. (2015) Age-related changes in intrinsic function of the superior temporal sulcus in autism spectrum disorders. Soc Cogn Affect Neurosci 10:1413-23
Konopaske, Glenn T; Coyle, Joseph T (2015) Possible compensatory mechanisms for glutamatergic disconnection found in the auditory cortex in schizophrenia. Biol Psychiatry 77:923-4
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
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
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

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