期刊
CEREBRAL CORTEX
卷 22, 期 8, 页码 1717-1727出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/cercor/bhr216
关键词
diabetes; insulin receptor signaling; long-term potentiation; NMDA receptor; synaptic plasticity
资金
- Ministerio de Ciencia e Innovacion [SAF2008-00011, BFU2007-60195, BFU2008-04196]
- CIBER de la Diabetes y Enfermedades Metabolicas, Instituto de Salud Carlos III
- Consejeria de Educacion Ciencia y Cultura of the Junta Cultural de Castilla-La Mancha (JCCM) [PAI07-0042-1097, PEII10-0095-872]
- Fundacion para la investigacion sanitaria de Castilla-La Mancha [PI-2007/49]
- Instituto de Salud Carlos HI [EMER-07/012]
- Regenerative Medicine Program of Valencia
- INCRECyT project from European Social Fund and JCCM
The beneficial effects of insulin and insulin-like growth factor I on cognition have been documented in humans and animal models. Conversely, obesity, hyperinsulinemia, and diabetes increase the risk for neurodegenerative disorders including Alzheimer's disease (AD). However, the mechanisms by which insulin regulates synaptic plasticity are not well understood. Here, we report that complete disruption of insulin receptor substrate 2 (Irs2) in mice impairs long-term potentiation (LTP) of synaptic transmission in the hippocampus. Basal synaptic transmission and paired-pulse facilitation were similar between the 2 groups of mice. Induction of LTP by high-frequency conditioning tetanus did not activate postsynaptic N-methyl-D-aspartate (NMDA) receptors in hippocampus slices from Irs2(-/-) mice, although the expression of NR2A, NR2B, and PSD95 was equivalent to wild-type controls. Activation of Fyn, Ala, and MAPK in response to tetanus stimulation was defective in Irs2(-/-) mice. Interestingly, IRS2 was phosphorylated during induction of LTP in control mice, revealing a potential new component of the signaling machinery which modulates synaptic plasticity. Given that IRS2 expression is diminished in Type 2 diabetics as well as in AD patients, these data may reveal an explanation for the prevalence of cognitive decline in humans with metabolic disorders by providing a mechanistic link between insulin resistance and impaired synaptic transmission.
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