ABSTRACT
Title
Impaired long-term synaptic plasticity in the hippocampus of mice heterozygous for insulin receptor
Authors
S. Piccinin1,2, S. Middei2, N. B. Mercuri2, M. D’Amelio2, R. Nisticò2,3
1 Department of Physiology and Pharmacology, University “Sapienza”, 00185 Rome, Italy
2 IRCSS SLucia Foundation, Rome 00143, Italy
3 Department of Pharmacobiology, University of Calabria, Rende (CS), Italy
1 Department of Physiology and Pharmacology, University “Sapienza”, 00185 Rome, Italy
2 IRCSS SLucia Foundation, Rome 00143, Italy
3 Department of Pharmacobiology, University of Calabria, Rende (CS), Italy
Abstract
The insulin receptor (IR) is a protein tyrosine kinase playing a pivotal role in regulation of peripheralglucose metabolism and energy homeostasis. Insulin receptors are also abundantly distributed in the cerebral cortex and hippocampus (Heidenreich, K. A., Zahniser, N. R., Berhanu, P., Brandenburg, D., and Olefsky, J. M., 1983 Structural differences between insulin receptors in the brain and peripheral target tissues. J. Biol. Chem. 258, 8527–8530), where they play a role in synaptic activities required for learning and memory (Zhao, W. Q., and Alkon, D. L. (2001) Role of insulin and insulin receptor in learning and memory. Mol. Cell. Endocrinol. 177, 125–134). As the major anabolic hormone in mammals, insulin stimulates protein synthesis partially through the activation of mTOR (mammalian target of rapamycin). mTOR is a phosphatidylinositol 3-kinase-related protein kinase that controls the phosphorylation of multiple factors involved in several cellular functions, including neuronal development, synaptic plasticity and memory (Hoeffer and Klann, TiNS, 2010). The mTOR pathway was first implicated in synapticplasticity when rapamycin, a selective inhibitor of mTORactivity was shown to prevent the late phase of long-term potentiation (L-LTP) in rat hippocampus (Tang et al., 2002; Cammalleri et al., 2003). Activation of mTOR by insulin has also been functionally linked with local protein synthesis in synapses, resulting in up-regulation of local PSD-95 (Lee et al., JBC 2005) and in the formation and maturation of new dendritic spines (Hoeffer and Klann, TiNS, 2010).
In this work, by means of a multidisciplinary approach, we evaluated hippocampal synaptic plasticity in mice heterozygous for the insulin receptor (Bruning et al., Cell1997). Interestingly, electrophysiological data show a reduction of L-LTP in the hippocampus that iscorrelated with alterations in the PSD structure and dendritic spine degeneration. The present findings highlight how thepharmacological modulation of insulin signaling, which can decline with aging and neurodegeneration, could have significant potential to prevent synaptic plasticity deficits associated to cognitive deterioration.
In this work, by means of a multidisciplinary approach, we evaluated hippocampal synaptic plasticity in mice heterozygous for the insulin receptor (Bruning et al., Cell1997). Interestingly, electrophysiological data show a reduction of L-LTP in the hippocampus that iscorrelated with alterations in the PSD structure and dendritic spine degeneration. The present findings highlight how thepharmacological modulation of insulin signaling, which can decline with aging and neurodegeneration, could have significant potential to prevent synaptic plasticity deficits associated to cognitive deterioration.