Development of antipsychotic medications with novel mechanisms of action based on computational modeling of hippocampal neuropathology.

A 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 medi...

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Autores principales:	Peter J Siekmeier, David P vanMaanen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/52b38aab149b40a3bbc80148cfde341a
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spelling	oai:doaj.org-article:52b38aab149b40a3bbc80148cfde341a2021-11-18T07:52:59ZDevelopment of antipsychotic medications with novel mechanisms of action based on computational modeling of hippocampal neuropathology.1932-620310.1371/journal.pone.0058607https://doaj.org/article/52b38aab149b40a3bbc80148cfde341a2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23526999/?tool=EBIhttps://doaj.org/toc/1932-6203A 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.Peter J SiekmeierDavid P vanMaanenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 3, p e58607 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Peter J Siekmeier David P vanMaanen Development of antipsychotic medications with novel mechanisms of action based on computational modeling of hippocampal neuropathology.
description	A 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.
format	article
author	Peter J Siekmeier David P vanMaanen
author_facet	Peter J Siekmeier David P vanMaanen
author_sort	Peter J Siekmeier
title	Development of antipsychotic medications with novel mechanisms of action based on computational modeling of hippocampal neuropathology.
title_short	Development of antipsychotic medications with novel mechanisms of action based on computational modeling of hippocampal neuropathology.
title_full	Development of antipsychotic medications with novel mechanisms of action based on computational modeling of hippocampal neuropathology.
title_fullStr	Development of antipsychotic medications with novel mechanisms of action based on computational modeling of hippocampal neuropathology.
title_full_unstemmed	Development of antipsychotic medications with novel mechanisms of action based on computational modeling of hippocampal neuropathology.
title_sort	development of antipsychotic medications with novel mechanisms of action based on computational modeling of hippocampal neuropathology.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/52b38aab149b40a3bbc80148cfde341a
work_keys_str_mv	AT peterjsiekmeier developmentofantipsychoticmedicationswithnovelmechanismsofactionbasedoncomputationalmodelingofhippocampalneuropathology AT davidpvanmaanen developmentofantipsychoticmedicationswithnovelmechanismsofactionbasedoncomputationalmodelingofhippocampalneuropathology
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Development of antipsychotic medications with novel mechanisms of action based on computational modeling of hippocampal neuropathology.

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