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Altered neuronal excitability underlies impaired hippocampal function in an animal model of psychosis

Psychosis is accompanied by severe attentional deficits, and impairments in associational-memory processing and sensory information processing that are ascribed to dysfunctions in prefrontal and hippocampal function. Disruptions of glutamatergic signaling may underlie these alterations: Antagonism o...

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Autores principales: Grüter, Thomas, Wiescholleck, Valentina, Dubovyk, Valentyna, Aliane, Verena, Manahan-Vaughan, Denise
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438226/
https://www.ncbi.nlm.nih.gov/pubmed/26042007
http://dx.doi.org/10.3389/fnbeh.2015.00117
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author Grüter, Thomas
Wiescholleck, Valentina
Dubovyk, Valentyna
Aliane, Verena
Manahan-Vaughan, Denise
author_facet Grüter, Thomas
Wiescholleck, Valentina
Dubovyk, Valentyna
Aliane, Verena
Manahan-Vaughan, Denise
author_sort Grüter, Thomas
collection PubMed
description Psychosis is accompanied by severe attentional deficits, and impairments in associational-memory processing and sensory information processing that are ascribed to dysfunctions in prefrontal and hippocampal function. Disruptions of glutamatergic signaling may underlie these alterations: Antagonism of the N-methyl-D-aspartate receptor (NMDAR) results in similar molecular, cellular, cognitive and behavioral changes in rodents and/or humans as those that occur in psychosis, raising the question as to whether changes in glutamatergic transmission may be intrinsic to the pathophysiology of the disease. In an animal model of psychosis that comprises treatment with the irreversible NMDAR-antagonist, MK801, we explored the cellular mechanisms that may underlie hippocampal dysfunction in psychosis. MK801-treatment resulted in a profound loss of hippocampal LTP that was evident 4 weeks after treatment. Whereas neuronal expression of the immediate early gene, Arc, was enhanced in the hippocampus by spatial learning in controls, MK801-treated animals failed to show activity-dependent increases in Arc expression. By contrast, a significant increase in basal Arc expression in the absence of learning was evident compared to controls. Paired-pulse (PP) facilitation was increased at the 40 ms interval indicating that NMDAR and/or fast GABAergic-mediated neurotransmission was disrupted. In line with this, MK801-treatment resulted in a significant decrease in GABA(A), and increase in GABA(B)-receptor-expression in PFC, along with a significant increase of GABA(B)- and NMDAR-GluN2B expression in the dentate gyrus. NMDAR-GluN1 or GluN2A subunit expression was unchanged. These data suggest that in psychosis, deficits in hippocampus-dependent memory may be caused by a loss of hippocampal LTP that arises through enhanced hippocampal neuronal excitability, altered GluN2B and GABA receptor expression and an uncoupling of the hippocampus-prefrontal cortex circuitry.
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spelling pubmed-44382262015-06-03 Altered neuronal excitability underlies impaired hippocampal function in an animal model of psychosis Grüter, Thomas Wiescholleck, Valentina Dubovyk, Valentyna Aliane, Verena Manahan-Vaughan, Denise Front Behav Neurosci Neuroscience Psychosis is accompanied by severe attentional deficits, and impairments in associational-memory processing and sensory information processing that are ascribed to dysfunctions in prefrontal and hippocampal function. Disruptions of glutamatergic signaling may underlie these alterations: Antagonism of the N-methyl-D-aspartate receptor (NMDAR) results in similar molecular, cellular, cognitive and behavioral changes in rodents and/or humans as those that occur in psychosis, raising the question as to whether changes in glutamatergic transmission may be intrinsic to the pathophysiology of the disease. In an animal model of psychosis that comprises treatment with the irreversible NMDAR-antagonist, MK801, we explored the cellular mechanisms that may underlie hippocampal dysfunction in psychosis. MK801-treatment resulted in a profound loss of hippocampal LTP that was evident 4 weeks after treatment. Whereas neuronal expression of the immediate early gene, Arc, was enhanced in the hippocampus by spatial learning in controls, MK801-treated animals failed to show activity-dependent increases in Arc expression. By contrast, a significant increase in basal Arc expression in the absence of learning was evident compared to controls. Paired-pulse (PP) facilitation was increased at the 40 ms interval indicating that NMDAR and/or fast GABAergic-mediated neurotransmission was disrupted. In line with this, MK801-treatment resulted in a significant decrease in GABA(A), and increase in GABA(B)-receptor-expression in PFC, along with a significant increase of GABA(B)- and NMDAR-GluN2B expression in the dentate gyrus. NMDAR-GluN1 or GluN2A subunit expression was unchanged. These data suggest that in psychosis, deficits in hippocampus-dependent memory may be caused by a loss of hippocampal LTP that arises through enhanced hippocampal neuronal excitability, altered GluN2B and GABA receptor expression and an uncoupling of the hippocampus-prefrontal cortex circuitry. Frontiers Media S.A. 2015-05-20 /pmc/articles/PMC4438226/ /pubmed/26042007 http://dx.doi.org/10.3389/fnbeh.2015.00117 Text en Copyright © 2015 Grüter, Wiescholleck, Dubovyk, Aliane and Manahan-Vaughan. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Grüter, Thomas
Wiescholleck, Valentina
Dubovyk, Valentyna
Aliane, Verena
Manahan-Vaughan, Denise
Altered neuronal excitability underlies impaired hippocampal function in an animal model of psychosis
title Altered neuronal excitability underlies impaired hippocampal function in an animal model of psychosis
title_full Altered neuronal excitability underlies impaired hippocampal function in an animal model of psychosis
title_fullStr Altered neuronal excitability underlies impaired hippocampal function in an animal model of psychosis
title_full_unstemmed Altered neuronal excitability underlies impaired hippocampal function in an animal model of psychosis
title_short Altered neuronal excitability underlies impaired hippocampal function in an animal model of psychosis
title_sort altered neuronal excitability underlies impaired hippocampal function in an animal model of psychosis
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438226/
https://www.ncbi.nlm.nih.gov/pubmed/26042007
http://dx.doi.org/10.3389/fnbeh.2015.00117
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