Brain deletion of insulin receptor substrate 2 disrupts hippocampal synaptic plasticity and metaplasticity.
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,...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3287998?pdf=render |
| _version_ | 1818028947477102592 |
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| author | Derek A Costello Marc Claret Hind Al-Qassab Florian Plattner Elaine E Irvine Agharul I Choudhury K Peter Giese Dominic J Withers Paola Pedarzani |
| author_facet | Derek A Costello Marc Claret Hind Al-Qassab Florian Plattner Elaine E Irvine Agharul I Choudhury K Peter Giese Dominic J Withers Paola Pedarzani |
| author_sort | Derek A Costello |
| collection | DOAJ |
| description | 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).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).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.These findings reveal molecular and cellular mechanisms that might underlie cognitive deficits linked to specific defects of neuronal insulin signalling. |
| first_indexed | 2024-12-10T05:11:53Z |
| format | Article |
| id | doaj.art-c9a0de9cd3fb4b4dbb4d7205f11dd116 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T05:11:53Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c9a0de9cd3fb4b4dbb4d7205f11dd1162022-12-22T02:01:05ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0172e3112410.1371/journal.pone.0031124Brain deletion of insulin receptor substrate 2 disrupts hippocampal synaptic plasticity and metaplasticity.Derek A CostelloMarc ClaretHind Al-QassabFlorian PlattnerElaine E IrvineAgharul I ChoudhuryK Peter GieseDominic J WithersPaola PedarzaniDiabetes 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).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).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.These findings reveal molecular and cellular mechanisms that might underlie cognitive deficits linked to specific defects of neuronal insulin signalling.http://europepmc.org/articles/PMC3287998?pdf=render |
| spellingShingle | Derek A Costello Marc Claret Hind Al-Qassab Florian Plattner Elaine E Irvine Agharul I Choudhury K Peter Giese Dominic J Withers Paola Pedarzani Brain deletion of insulin receptor substrate 2 disrupts hippocampal synaptic plasticity and metaplasticity. PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC3287998?pdf=render |
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