title: Hippocampal Insulin Resistance Impairs Spatial Learning and Synaptic Plasticity.
abstract: Insulin receptors (IRs) are expressed in discrete neuronal populations in the central nervous system, including the hippocampus. To elucidate the functional role of hippocampal IRs independent of metabolic function, we generated a model of hippocampal-specific insulin resistance using a lentiviral vector expressing an IR antisense sequence (LV-IRAS). LV-IRAS effectively downregulates IR expression in the rat hippocampus without affecting body weight, adiposity, or peripheral glucose homeostasis. Nevertheless, hippocampal neuroplasticity was impaired in LV-IRAS-treated rats. High-frequency stimulation, which evoked robust long-term potentiation (LTP) in brain slices from LV control rats, failed to evoke LTP in LV-IRAS-treated rats. GluN2B subunit levels, as well as the basal level of phosphorylation of GluA1, were reduced in the hippocampus of LV-IRAS rats. Moreover, these deficits in synaptic transmission were associated with impairments in spatial learning. We suggest that alterations in the expression and phosphorylation of glutamate receptor subunits underlie the alterations in LTP and that these changes are responsible for the impairment in hippocampal-dependent learning. Importantly, these learning deficits are strikingly similar to the impairments in complex task performance observed in patients with diabetes, which strengthens the hypothesis that hippocampal insulin resistance is a key mediator of cognitive deficits independent of glycemic control.
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC cgrillo@uscmed.sc.edu.
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Grillo
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC.
authors.forename: Gerardo G
authors.initials: GG
authors.lastname: Piroli
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC Department of Psychology, University of South Carolina, Columbia, SC.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Lawrence
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC.
authors.forename: Shayna A
authors.initials: SA
authors.lastname: Wrighten
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC.
authors.forename: Adrienne J
authors.initials: AJ
authors.lastname: Green
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Wilson
authors.affiliation: Department of Psychiatry, University of Cincinnati Medical Center, Cincinnati, OH.
authors.forename: Randall R
authors.initials: RR
authors.lastname: Sakai
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC Department of Psychology, University of South Carolina, Columbia, SC.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Kelly
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC William Jennings Bryan Dorn Veterans Affairs Medical Center, Columbia, SC.
authors.forename: Marlene A
authors.initials: MA
authors.lastname: Wilson
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC.
authors.forename: David D
authors.initials: DD
authors.lastname: Mott
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC William Jennings Bryan Dorn Veterans Affairs Medical Center, Columbia, SC.
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Reagan
mesh_terms: D000818:Animals; D006624:Hippocampus / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D009473:Neuronal Plasticity / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D065853:Spatial Learning / Q000502:physiology*
chemical_list: D011972:Receptor, Insulin; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor