Brain deletion of insulin receptor substrate 2 disrupts hippocampal synaptic plasticity and metaplasticity

Derek A. Costello, Marc Claret, Hind Al-Qassab, Florian Plattner, Elaine E. Irvine, Agharul I. Choudhury, K. Peter Giese, Dominic J. Withers, Paola Pedarzani

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere31124
JournalPLoS One
Volume7
Issue number2
DOIs
StatePublished - Feb 27 2012

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Insulin Receptor Substrate Proteins
Neuronal Plasticity
Plasticity
Brain
brain
insulin
hyperglycemia
hippocampus
Insulin
Hyperglycemia
Hippocampus
receptors
dementia
mice
phosphatidylinositol 3-kinase
Glycogen Synthase Kinase 3
synapse
diabetes mellitus
Defects
Phosphorylation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Costello, D. A., Claret, M., Al-Qassab, H., Plattner, F., Irvine, E. E., Choudhury, A. I., ... Pedarzani, P. (2012). Brain deletion of insulin receptor substrate 2 disrupts hippocampal synaptic plasticity and metaplasticity. PLoS One, 7(2), [e31124]. https://doi.org/10.1371/journal.pone.0031124

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.

In: PLoS One, Vol. 7, No. 2, e31124, 27.02.2012.

Research output: Contribution to journalArticle

Costello, DA, Claret, M, Al-Qassab, H, Plattner, F, Irvine, EE, Choudhury, AI, Giese, KP, Withers, DJ & Pedarzani, P 2012, 'Brain deletion of insulin receptor substrate 2 disrupts hippocampal synaptic plasticity and metaplasticity', PLoS One, vol. 7, no. 2, e31124. https://doi.org/10.1371/journal.pone.0031124
Costello DA, Claret M, Al-Qassab H, Plattner F, Irvine EE, Choudhury AI et al. Brain deletion of insulin receptor substrate 2 disrupts hippocampal synaptic plasticity and metaplasticity. PLoS One. 2012 Feb 27;7(2). e31124. https://doi.org/10.1371/journal.pone.0031124
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. In: PLoS One. 2012 ; Vol. 7, No. 2.
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