title: IRS-2 Deficiency impairs NMDA receptor-dependent long-term potentiation.
abstract: 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, AKT, 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.
authors.affiliation: Laboratory of Neurophysiology and Synaptic Plasticity, Albacete Science and Technology Park, PCYTA, Institute for Research in Neurological Disabilities, University of Castilla-La Mancha, 02071 Albacete, Spain.
authors.forename: Eduardo D
authors.initials: ED
authors.lastname: Martín
authors.forename: Ana
authors.initials: A
authors.lastname: Sánchez-Perez
authors.forename: José Luis
authors.initials: JL
authors.lastname: Trejo
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Martin-Aldana
authors.forename: Marife
authors.initials: M
authors.lastname: Cano Jaimez
authors.forename: Sebastián
authors.initials: S
authors.lastname: Pons
authors.forename: Carlos
authors.initials: C
authors.lastname: Acosta Umanzor
authors.forename: Lorena
authors.initials: L
authors.lastname: Menes
authors.forename: Morris F
authors.initials: MF
authors.lastname: White
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Burks
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D047468:Immunoprecipitation; D055504:Insulin Receptor Substrate Proteins / Q000172:deficiency / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D016194:Receptors, N-Methyl-D-Aspartate