Brain deletion of insulin receptor substrate 2 disrupts hippocampal synaptic plasticity and metaplasticity
Citation:
Costello, D.A., Claret, M., Al-Qassab, H., Plattner, F., Irvine, E.E., Choudhury, A.I., Giese, K.P., (...), Pedarzani, P., Brain deletion of insulin receptor substrate 2 disrupts hippocampal synaptic plasticity and metaplasticity, Plos One, 7, 2, 2012, art. no. e31124Download Item:
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-3
b
.
Conclusions:
These findings reveal molecular and cellular mechanisms that might underlie cognitive deficits linked to
specific defects of neuronal insulin signalling.
Sponsor
Grant Number
Medical Research Council (MRC)
G0100066
Biotechnology and Biological Sciences Research Council (BBSRC)
BBS/B/16143
Author's Homepage:
http://people.tcd.ie/decostelDescription:
PUBLISHED
Author: COSTELLO, DEREK
Type of material:
Journal ArticleSeries/Report no:
Plos One;7;
2;
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