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Glutamate Deregulation in Ketamine-Induced Psychosis—A Potential Role of PSD95, NMDA Receptor and PMCA Interaction

Ketamine causes psychotic episodes and is often used as pharmacological model of psychotic-like behavior in animals. There is increasing evidence that molecular mechanism of its action is more complicated than just N-methyl-D-aspartic acid (NMDA) receptor antagonism and involves interaction with the...

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Autores principales: Lisek, Malwina, Ferenc, Bozena, Studzian, Maciej, Pulaski, Lukasz, Guo, Feng, Zylinska, Ludmila, Boczek, Tomasz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487377/
https://www.ncbi.nlm.nih.gov/pubmed/28701926
http://dx.doi.org/10.3389/fncel.2017.00181
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author Lisek, Malwina
Ferenc, Bozena
Studzian, Maciej
Pulaski, Lukasz
Guo, Feng
Zylinska, Ludmila
Boczek, Tomasz
author_facet Lisek, Malwina
Ferenc, Bozena
Studzian, Maciej
Pulaski, Lukasz
Guo, Feng
Zylinska, Ludmila
Boczek, Tomasz
author_sort Lisek, Malwina
collection PubMed
description Ketamine causes psychotic episodes and is often used as pharmacological model of psychotic-like behavior in animals. There is increasing evidence that molecular mechanism of its action is more complicated than just N-methyl-D-aspartic acid (NMDA) receptor antagonism and involves interaction with the components of calcium homeostatic machinery, in particular plasma membrane calcium pump (PMCA). Therefore, in this study we aimed to characterize brain region-specific effects of ketamine on PMCA activity, interaction with NMDA receptor through postsynaptic density protein 95 (PSD95) scaffolding proteins and glutamate release from nerve endings. In our study, ketamine induced behavioral changes in healthy male rats consistent with psychotic effects. In the same animals, we were able to demonstrate significant inhibition of plasma membrane calcium ATPase (PMCA) activity in cerebellum, hippocampus and striatum. The expression level and isoform composition of PMCAs were also affected in some of these brain compartments, with possible compensatory effects of PMCA1 substituting for decreased expression of PMCA3. Expression of the PDZ domain-containing scaffold protein PSD95 was induced and its association with PMCA4 was higher in most brain compartments upon ketamine treatment. Moreover, increased PSD95/NMDA receptor direct interaction was also reported, strongly suggesting the formation of multiprotein complexes potentially mediating the effect of ketamine on calcium signaling. We further support this molecular mechanism by showing brain region-specific changes in PSD95/PMCA4 spatial colocalization. We also show that ketamine significantly increases synaptic glutamate release in cortex and striatum (without affecting total tissue glutamate content), inducing the expression of vesicular glutamate transporters and decreasing the expression of membrane glutamate reuptake pump excitatory amino acid transporters 2 (EAAT2). Thus, ketamine-mediated PMCA inhibition, by decreasing total Ca(2+) clearing potency, may locally raise cytosolic Ca(2+) promoting excessive glutamate release. Regional alterations in glutamate secretion can be further driven by PSD95-mediated spatial recruitment of signaling complexes including glutamate receptors and calcium pumps, representing a novel mechanism of psychogenic action of ketamine.
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spelling pubmed-54873772017-07-12 Glutamate Deregulation in Ketamine-Induced Psychosis—A Potential Role of PSD95, NMDA Receptor and PMCA Interaction Lisek, Malwina Ferenc, Bozena Studzian, Maciej Pulaski, Lukasz Guo, Feng Zylinska, Ludmila Boczek, Tomasz Front Cell Neurosci Neuroscience Ketamine causes psychotic episodes and is often used as pharmacological model of psychotic-like behavior in animals. There is increasing evidence that molecular mechanism of its action is more complicated than just N-methyl-D-aspartic acid (NMDA) receptor antagonism and involves interaction with the components of calcium homeostatic machinery, in particular plasma membrane calcium pump (PMCA). Therefore, in this study we aimed to characterize brain region-specific effects of ketamine on PMCA activity, interaction with NMDA receptor through postsynaptic density protein 95 (PSD95) scaffolding proteins and glutamate release from nerve endings. In our study, ketamine induced behavioral changes in healthy male rats consistent with psychotic effects. In the same animals, we were able to demonstrate significant inhibition of plasma membrane calcium ATPase (PMCA) activity in cerebellum, hippocampus and striatum. The expression level and isoform composition of PMCAs were also affected in some of these brain compartments, with possible compensatory effects of PMCA1 substituting for decreased expression of PMCA3. Expression of the PDZ domain-containing scaffold protein PSD95 was induced and its association with PMCA4 was higher in most brain compartments upon ketamine treatment. Moreover, increased PSD95/NMDA receptor direct interaction was also reported, strongly suggesting the formation of multiprotein complexes potentially mediating the effect of ketamine on calcium signaling. We further support this molecular mechanism by showing brain region-specific changes in PSD95/PMCA4 spatial colocalization. We also show that ketamine significantly increases synaptic glutamate release in cortex and striatum (without affecting total tissue glutamate content), inducing the expression of vesicular glutamate transporters and decreasing the expression of membrane glutamate reuptake pump excitatory amino acid transporters 2 (EAAT2). Thus, ketamine-mediated PMCA inhibition, by decreasing total Ca(2+) clearing potency, may locally raise cytosolic Ca(2+) promoting excessive glutamate release. Regional alterations in glutamate secretion can be further driven by PSD95-mediated spatial recruitment of signaling complexes including glutamate receptors and calcium pumps, representing a novel mechanism of psychogenic action of ketamine. Frontiers Media S.A. 2017-06-28 /pmc/articles/PMC5487377/ /pubmed/28701926 http://dx.doi.org/10.3389/fncel.2017.00181 Text en Copyright © 2017 Lisek, Ferenc, Studzian, Pulaski, Guo, Zylinska and Boczek. 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 or 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
Lisek, Malwina
Ferenc, Bozena
Studzian, Maciej
Pulaski, Lukasz
Guo, Feng
Zylinska, Ludmila
Boczek, Tomasz
Glutamate Deregulation in Ketamine-Induced Psychosis—A Potential Role of PSD95, NMDA Receptor and PMCA Interaction
title Glutamate Deregulation in Ketamine-Induced Psychosis—A Potential Role of PSD95, NMDA Receptor and PMCA Interaction
title_full Glutamate Deregulation in Ketamine-Induced Psychosis—A Potential Role of PSD95, NMDA Receptor and PMCA Interaction
title_fullStr Glutamate Deregulation in Ketamine-Induced Psychosis—A Potential Role of PSD95, NMDA Receptor and PMCA Interaction
title_full_unstemmed Glutamate Deregulation in Ketamine-Induced Psychosis—A Potential Role of PSD95, NMDA Receptor and PMCA Interaction
title_short Glutamate Deregulation in Ketamine-Induced Psychosis—A Potential Role of PSD95, NMDA Receptor and PMCA Interaction
title_sort glutamate deregulation in ketamine-induced psychosis—a potential role of psd95, nmda receptor and pmca interaction
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487377/
https://www.ncbi.nlm.nih.gov/pubmed/28701926
http://dx.doi.org/10.3389/fncel.2017.00181
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