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dc.contributor.authorSiekmeier, Peter J.
dc.contributor.authorvan Maanen, David P
dc.date.accessioned2013-04-29T20:00:42Z
dc.date.issued2013
dc.identifier.citationSiekmeier, Peter J., and David P. vanMaanen. 2013. Development of antipsychotic medications with novel mechanisms of action based on computational modeling of hippocampal neuropathology. PLoS ONE 8(3): e58607.en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10591656
dc.description.abstractA large number of cellular level abnormalities have been identified in the hippocampus of schizophrenic subjects. Nonetheless, it remains uncertain how these pathologies interact at a system level to create clinical symptoms, and this has hindered the development of more effective antipsychotic medications. Using a 72-processor supercomputer, we created a tissue level hippocampal simulation, featuring multicompartmental neuron models with multiple ion channel subtypes and synaptic channels with realistic temporal dynamics. As an index of the schizophrenic phenotype, we used the specific inability of the model to attune to 40 Hz (gamma band) stimulation, a well-characterized abnormality in schizophrenia. We examined several possible combinations of putatively schizophrenogenic cellular lesions by systematically varying model parameters representing NMDA channel function, dendritic spine density, and GABA system integrity, conducting 910 trials in total. Two discrete “clusters” of neuropathological changes were identified. The most robust was characterized by co-occurring modest reductions in NMDA system function (-30%) and dendritic spine density (-30%). Another set of lesions had greater NMDA hypofunction along with low level GABA system dysregulation. To the schizophrenic model, we applied the effects of 1,500 virtual medications, which were implemented by varying five model parameters, independently, in a graded manner; the effects of known drugs were also applied. The simulation accurately distinguished agents that are known to lack clinical efficacy, and identified novel mechanisms (e.g., decrease in AMPA conductance decay time constant, increase in projection strength of calretinin-positive interneurons) and combinations of mechanisms that could re-equilibrate model behavior. These findings shed light on the mechanistic links between schizophrenic neuropathology and the gamma band oscillatory abnormalities observed in the illness. As such, they generate specific falsifiable hypotheses, which can guide postmortem and other laboratory research. Significantly, this work also suggests specific non-obvious targets for potential pharmacologic agents.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pone.0058607en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3602393/pdf/en_US
dash.licenseLAA
dc.subjectBiologyen_US
dc.subjectBiophysicsen_US
dc.subjectBiophysics Simulationsen_US
dc.subjectNeuroscienceen_US
dc.subjectNeurophysiologyen_US
dc.subjectCentral Nervous Systemen_US
dc.subjectSynapsesen_US
dc.subjectComputational Neuroscienceen_US
dc.subjectNeural Networksen_US
dc.subjectNeuroanatomyen_US
dc.subjectNeurobiology of Disease and Regenerationen_US
dc.subjectNeurotransmittersen_US
dc.subjectSystems Biologyen_US
dc.subjectMedicineen_US
dc.subjectDrugs and Devicesen_US
dc.subjectDrug Research and Developmenten_US
dc.subjectDrug Discoveryen_US
dc.subjectPsychopharmacologyen_US
dc.subjectMental Healthen_US
dc.subjectPsychiatryen_US
dc.subjectSchizophreniaen_US
dc.titleDevelopment of Antipsychotic Medications with Novel Mechanisms of Action Based on Computational Modeling of Hippocampal Neuropathologyen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS ONEen_US
dash.depositing.authorvan Maanen, David P
dc.date.available2013-04-29T20:00:42Z
dc.identifier.doi10.1371/journal.pone.0058607*
dash.authorsorderedfalse
dash.contributor.affiliatedvan Maanen, David P
dash.contributor.affiliatedSiekmeier, Peter


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