Insulin Receptor β-Subunit Haploinsufficiency Impairs Hippocampal Late-Phase LTP and Recognition Memory

Nisticò, Robert; Cavallucci, Virve; Piccinin, Sonia; Macrı̀, Simone; Pignatelli, Marco; Mehdawy, Bisan; Blandini, Fabio; Laviola, Giovanni; Lauro, Davide; Mercuri, Nicola Biagio; D’Amelio, Marcello

doi:10.1007/s12017-012-8184-z

Cited by 61 publications

(42 citation statements)

References 41 publications

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“…The InR has a role in cognitive function such that reduced activity of this receptor in the hippocampus impairs long-term potentiation consistent with poor recognition memory. 34 Our data similarly show that the detrimental effects of fructose on hippocampal InR signaling were commensurable to poor performance in the Barnes maze. In addition, fructose consumption reduced phosphorylation of IRS-1 in TBI animals suggesting that impaired insulin signaling can compromise the outcome of TBI.…”

Section: Discussionsupporting

confidence: 66%

Dietary fructose aggravates the pathobiology of traumatic brain injury by influencing energy homeostasis and plasticity

Agrawal

Noble

Vergnes

et al. 2015

J Cereb Blood Flow Metab

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Fructose consumption has been on the rise for the last two decades and is starting to be recognized as being responsible for metabolic diseases. Metabolic disorders pose a particular threat for brain conditions characterized by energy dysfunction, such as traumatic brain injury. Traumatic brain injury patients experience sudden abnormalities in the control of brain metabolism and cognitive function, which may worsen the prospect of brain plasticity and function. The mechanisms involved are poorly understood. Here we report that fructose consumption disrupts hippocampal energy homeostasis as evidenced by a decline in functional mitochondria bioenergetics (oxygen consumption rate and cytochrome C oxidase activity) and an aggravation of the effects of traumatic brain injury on molecular systems engaged in cell energy homeostasis (sirtuin 1, peroxisome proliferator-activated receptor gamma coactivator-1alpha) and synaptic plasticity (brainderived neurotrophic factor, tropomyosin receptor kinase B, cyclic adenosine monophosphate response element binding, synaptophysin signaling). Fructose also worsened the effects of traumatic brain injury on spatial memory, which disruption was associated with a decrease in hippocampal insulin receptor signaling. Additionally, fructose consumption and traumatic brain injury promoted plasma membrane lipid peroxidation, measured by elevated protein and phenotypic expression of 4-hydroxynonenal. These data imply that high fructose consumption exacerbates the pathology of brain trauma by further disrupting energy metabolism and brain plasticity, highlighting the impact of diet on the resilience to neurological disorders.

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Section: Discussionsupporting

confidence: 66%

Dietary fructose aggravates the pathobiology of traumatic brain injury by influencing energy homeostasis and plasticity

Agrawal

Noble

Vergnes

et al. 2015

J Cereb Blood Flow Metab

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“…Supporting these findings, high energy diets have been previously shown to influence GLUT2 [83] as well as IR expression in the brain [84]. A positive effect of GLUT2 on hippocampal synaptic activity, neurotransmitter release, and cognition has been previously reported [85, 86], while others have suggested involvement of insulin receptors in hippocampal dependent spatial learning and memory [87–89] as well as recognition memory [90–92]. In another series of studies, intracerebroventricular injection of streptozotocin, a drug specific to GLUT2 dependent transport [93], was shown to decrease IR expression only in the CA3 region of the rat’s hippocampus [94], and was found to be associated with memory impairments [95].…”

Section: Discussionmentioning

confidence: 73%

Cognitive impairment and gene expression alterations in a rodent model of binge eating disorder

Chawla

Cordner

Boersma

et al. 2017

Physiology & Behavior

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Binge eating disorder (BED) is defined as recurrent, distressing over-consumption of palatable food (PF) in a short time period. Clinical studies suggest that individuals with BED may have impairments in cognitive processes, executive functioning, impulse control, and decision-making, which may play a role in sustaining binge eating behavior. These clinical reports, however, are limited and often conflicting. In this study, we used a limited access rat model of binge-like behavior in order to further explore the effects of binge eating on cognition. In binge eating prone (BEP) rats, we found novel object recognition (NOR) as well as Barnes maze reversal learning (BM-RL) deficits. Aberrant gene expression of brain derived neurotrophic factor (Bdnf) and tropomyosin receptor kinase B (TrkB) in the hippocampus (HPC)-prefrontal cortex (PFC) network was observed in BEP rats. Additionally, the NOR deficits were correlated with reductions in the expression of TrkB and insulin receptor (Ir) in the CA3 region of the hippocampus. Furthermore, up-regulation of serotonin-2C (5-HT2C) receptors in the orbitoprefrontal cortex (OFC) were associated with BM-RL deficit. Finally, in the nucleus accumbens (NAc), we found decreased dopamine receptor 2 (Drd2) expression among BEP rats. Taken together, these data suggest that binge eating vegetable shortening may induce contextual and reversal learning deficits which may be mediated, at least in part, by the altered expression of genes in the CA3-OFC-NAc neural network.

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“…Mice engineered without the glucagon-like peptide 1 (GLP-1) receptor had reduced LTP in area CA1 of the hippocampus, showed impaired discrimination of learned and novel objects and performed poorly on a water maze task [36]. Similarly, reducing insulin receptor expression globally by means of β-subunit haploinsufficiency [37] or in the hippocampus using a lentiviral vector [38] severely curtailed hippocampal LTP and impaired spatial memory. What makes the present results notable is that plasticity was assessed in the motor cortex, while learning and memory are hippocampal-dependent and working memory is most closely associated with lateral prefrontal and posterior parietal cortices.…”

Section: Discussionmentioning

confidence: 99%

Humans with Type-2 Diabetes Show Abnormal Long-Term Potentiation-Like Cortical Plasticity Associated with Verbal Learning Deficits

Fried

Schilberg

Brem

et al. 2016

JAD

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Background Type-2 diabetes mellitus (T2DM) accelerates cognitive aging and increases risk of Alzheimer’s disease. Rodent models of T2DM show altered synaptic plasticity associated with reduced learning and memory. Humans with T2DM also show cognitive deficits, including reduced learning and memory, but the relationship of these impairments to the efficacy of neuroplastic mechanisms has never been assessed. Objective Our primary objective was to compare mechanisms of cortical plasticity in humans with and without T2DM. Our secondary objective was to relate plasticity measures to standard measures of cognition. Methods A prospective cross-sectional cohort study was conducted on 21 adults with T2DM and 15 demographically-similar non-diabetic controls. Long-term potentiation-like plasticity was assessed in primary motor cortex by comparing the amplitude of motor evoked potentials (MEPs) from single-pulse transcranial magnetic stimulation before and after intermittent theta-burst stimulation (iTBS). Plasticity measures were compared between groups and related to neuropsychological scores. Results In T2DM, iTBS-induced modulation of MEPs was significantly less than controls, even after controlling for potential confounds. Furthermore, in T2DM, modulation of MEPs 10-min post-iTBS was significantly correlated with Rey Auditory Verbal Learning Task (RAVLT) performance. Conclusion Humans with T2DM show abnormal cortico-motor plasticity that is correlated with reduced verbal learning. Since iTBS after-effects and the RAVLT are both NMDA receptor-dependent measures, their relationship in T2DM may reflect brain-wide alterations in the efficacy of NMDA receptors. These findings offer novel mechanistic insights into the brain consequences of T2DM and provide a reliable means to monitor brain health and evaluate the efficacy of clinical interventions.

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Insulin Receptor β-Subunit Haploinsufficiency Impairs Hippocampal Late-Phase LTP and Recognition Memory

Cited by 61 publications

References 41 publications

Dietary fructose aggravates the pathobiology of traumatic brain injury by influencing energy homeostasis and plasticity

Dietary fructose aggravates the pathobiology of traumatic brain injury by influencing energy homeostasis and plasticity

Cognitive impairment and gene expression alterations in a rodent model of binge eating disorder

Humans with Type-2 Diabetes Show Abnormal Long-Term Potentiation-Like Cortical Plasticity Associated with Verbal Learning Deficits

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