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Brain Deletion of Insulin Receptor Substrate 2 Disrupts Hippocampal Synaptic Plasticity and Metaplasticity

OBJECTIVE: Diabetes mellitus is associated with cognitive deficits and an increased risk of dementia, particularly in the elderly. These deficits and the corresponding neurophysiological structural and functional alterations are linked to both metabolic and vascular changes, related to chronic hyper...

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Autores principales: Costello, Derek A., Claret, Marc, Al-Qassab, Hind, Plattner, Florian, Irvine, Elaine E., Choudhury, Agharul I., Giese, K. Peter, Withers, Dominic J., Pedarzani, Paola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3287998/
https://www.ncbi.nlm.nih.gov/pubmed/22383997
http://dx.doi.org/10.1371/journal.pone.0031124
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author Costello, Derek A.
Claret, Marc
Al-Qassab, Hind
Plattner, Florian
Irvine, Elaine E.
Choudhury, Agharul I.
Giese, K. Peter
Withers, Dominic J.
Pedarzani, Paola
author_facet Costello, Derek A.
Claret, Marc
Al-Qassab, Hind
Plattner, Florian
Irvine, Elaine E.
Choudhury, Agharul I.
Giese, K. Peter
Withers, Dominic J.
Pedarzani, Paola
author_sort Costello, Derek A.
collection PubMed
description OBJECTIVE: Diabetes mellitus is associated with cognitive deficits and an increased risk of dementia, particularly in the elderly. These deficits and the corresponding neurophysiological structural and functional alterations are linked to both metabolic and vascular changes, related to chronic hyperglycaemia, but probably also defects in insulin action in the brain. To elucidate the specific role of brain insulin signalling in neuronal functions that are relevant for cognitive processes we have investigated the behaviour of neurons and synaptic plasticity in the hippocampus of mice lacking the insulin receptor substrate protein 2 (IRS-2). RESEARCH DESIGN AND METHODS: To study neuronal function and synaptic plasticity in the absence of confounding factors such as hyperglycaemia, we used a mouse model with a central nervous system- (CNS)-restricted deletion of IRS-2 (NesCreIrs2KO). RESULTS: We report a deficit in NMDA receptor-dependent synaptic plasticity in the hippocampus of NesCreIrs2KO mice, with a concomitant loss of metaplasticity, the modulation of synaptic plasticity by the previous activity of a synapse. These plasticity changes are associated with reduced basal phosphorylation of the NMDA receptor subunit NR1 and of downstream targets of the PI3K pathway, the protein kinases Akt and GSK-3β. CONCLUSIONS: These findings reveal molecular and cellular mechanisms that might underlie cognitive deficits linked to specific defects of neuronal insulin signalling.
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spelling pubmed-32879982012-03-01 Brain Deletion of Insulin Receptor Substrate 2 Disrupts Hippocampal Synaptic Plasticity and Metaplasticity Costello, Derek A. Claret, Marc Al-Qassab, Hind Plattner, Florian Irvine, Elaine E. Choudhury, Agharul I. Giese, K. Peter Withers, Dominic J. Pedarzani, Paola PLoS One Research Article OBJECTIVE: Diabetes mellitus is associated with cognitive deficits and an increased risk of dementia, particularly in the elderly. These deficits and the corresponding neurophysiological structural and functional alterations are linked to both metabolic and vascular changes, related to chronic hyperglycaemia, but probably also defects in insulin action in the brain. To elucidate the specific role of brain insulin signalling in neuronal functions that are relevant for cognitive processes we have investigated the behaviour of neurons and synaptic plasticity in the hippocampus of mice lacking the insulin receptor substrate protein 2 (IRS-2). RESEARCH DESIGN AND METHODS: To study neuronal function and synaptic plasticity in the absence of confounding factors such as hyperglycaemia, we used a mouse model with a central nervous system- (CNS)-restricted deletion of IRS-2 (NesCreIrs2KO). RESULTS: We report a deficit in NMDA receptor-dependent synaptic plasticity in the hippocampus of NesCreIrs2KO mice, with a concomitant loss of metaplasticity, the modulation of synaptic plasticity by the previous activity of a synapse. These plasticity changes are associated with reduced basal phosphorylation of the NMDA receptor subunit NR1 and of downstream targets of the PI3K pathway, the protein kinases Akt and GSK-3β. CONCLUSIONS: These findings reveal molecular and cellular mechanisms that might underlie cognitive deficits linked to specific defects of neuronal insulin signalling. Public Library of Science 2012-02-27 /pmc/articles/PMC3287998/ /pubmed/22383997 http://dx.doi.org/10.1371/journal.pone.0031124 Text en Costello et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Costello, Derek A.
Claret, Marc
Al-Qassab, Hind
Plattner, Florian
Irvine, Elaine E.
Choudhury, Agharul I.
Giese, K. Peter
Withers, Dominic J.
Pedarzani, Paola
Brain Deletion of Insulin Receptor Substrate 2 Disrupts Hippocampal Synaptic Plasticity and Metaplasticity
title Brain Deletion of Insulin Receptor Substrate 2 Disrupts Hippocampal Synaptic Plasticity and Metaplasticity
title_full Brain Deletion of Insulin Receptor Substrate 2 Disrupts Hippocampal Synaptic Plasticity and Metaplasticity
title_fullStr Brain Deletion of Insulin Receptor Substrate 2 Disrupts Hippocampal Synaptic Plasticity and Metaplasticity
title_full_unstemmed Brain Deletion of Insulin Receptor Substrate 2 Disrupts Hippocampal Synaptic Plasticity and Metaplasticity
title_short Brain Deletion of Insulin Receptor Substrate 2 Disrupts Hippocampal Synaptic Plasticity and Metaplasticity
title_sort brain deletion of insulin receptor substrate 2 disrupts hippocampal synaptic plasticity and metaplasticity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3287998/
https://www.ncbi.nlm.nih.gov/pubmed/22383997
http://dx.doi.org/10.1371/journal.pone.0031124
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