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.

Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling

“…This observation is consistent with published studies demonstrating that insulin‐mediated activation of Akt signaling is impaired in Irs2 −/− mice (Withers et al 1998; Burks et al 2000). Also in line with our findings that IRS2 is required for CAF LTP, IRS2 deficient mice have impaired hippocampal synaptic plasticity in other paradigms (Costello et al 2012; Martín et al 2012). Thus, we conclude that IRS2 is necessary to mediate PI3K‐dependent pathways leading to CAF LTP.…”

“…Interestingly, IRS2 signals have been reported to mediate the action of BDNF (Yamada et al 1997) and hippocampal IRS2 is critical for LTP induction upon tetanic stimulation (Martín et al 2012). Because PI3K activity is necessary for CAF LTP (Fig.…”

“…IRS proteins are phosphorylated by active tyrosine kinase receptors, like insulin receptor (IR) and the insulin‐like growth factor‐1 receptor (IGF‐1R), and thereby regulate the cellular response by recruiting downstream signaling components such as phosphoinositide 3‐kinase (PI3K) and Akt (Myers et al 1992; White 2006). Importantly, mice deficient for IRS2 display defects in hippocampal synaptic plasticity (Costello et al 2012; Martín et al 2012). …”

Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates

“…Because of its multiple functions, regulation of IRS2 may be important in the linkages between stress, psychopathology, and the development of associated physiological alterations such as metabolic syndrome and type 2 diabetes. In the periphery, IRS2 regulates insulin sensitivity and in the brain IRS2 impacts multiple functions including reward (58), memory (59,60), and energy homeostasis (61,62). Moreover, type 2 diabetes has been associated with amygdala atrophy (63), and bidirectional associations between insulin resistance and affective disorders have been reported (64)(65)(66).…”

Insulin in the Brain: Sources, Localization and Functions

“…In another series of studies, the effects of insulin on long-term potentiation (LTP) have been investigated. Martin et al [174] have shown that induction of LTP causes IRS-2 to be phosphorylated. On the other hand, it has been reported that LTP in slice preparation from IRS-2 knockout mice is impaired [174] and that insulin improves the LTP impairment induced by beta amyloid in the CA1 region of rat hippocampal slices [175].…”