Effects of insulin on long-term potentiation in hippocampal slices from diabetic rats

Izumi, Yukitoshi; Yamada, Kelvin A.; Matsukawa, Mio; Zorumski, Charles F.

doi:10.1007/s00125-003-1144-2

Cited by 54 publications

(31 citation statements)

References 54 publications

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“…In this regard, changes in local glucose concentrations can alter the firing rate of some types of CNS neurons (i.e., hypothalamic). However, in one study, elevating local glucose concentrations from 5 to 30 mmol/l had no effect on long-term potentiation in healthy CA1 hippocampal neurons, suggesting that hyperglycemia alone may be insufficient to initiate cortical decline in the diabetic patient (44). Decreases in central insulin content or compensatory changes of cortical insulin (or other) neurotrophic receptor expression may contribute to CNS decline in the insulin-dependent diabetic patient.…”

Section: Discussionmentioning

confidence: 95%

Experimental Diabetes Attenuates Cerebral Cortical−Evoked Forelimb Motor Responses

et al. 2005

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Poorly controlled diabetes leads to debilitating peripheral complications, including retinopathy, nephropathy, and neuropathy. Chronic diabetes also impairs the central nervous system (CNS), leading to measurable deficits in cognition, somatosensory, and motor function. The cause of diabetes-associated CNS impairment is unknown. In this study, sustained hyperglycemia resulting from insulin deficiency was shown to contribute to CNS motor dysfunction. Experimental diabetes was induced in rats by streptozotocin (STZ) injection. CNS motor function was assessed by intracortical microstimulation of the sensorimotor cortex. Experimental diabetes significantly (P < 0.01; n ‫؍‬ 14) attenuated the number of motor cortical sites eliciting forelimb movements. The net area of the motor cortex representing the forelimb in diabetic rats was significantly reduced

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Section: Discussionmentioning

confidence: 95%

Experimental Diabetes Attenuates Cerebral Cortical−Evoked Forelimb Motor Responses

et al. 2005

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“…It is established that the well-known cerebrovascular complications of non-insulin-dependent diabetes mellitus (Ott et al, 1999;Stewart & Liolitsa, 1999;Wannamethee et al, 1999) interact with AD pathology in causing cognitive decline (Schneider et al, 2007). In addition, there is an emerging role of insulin in the regulation of synaptic plasticity (Plitzko et al, 2001;Skeberdis et al, 2001;Huang et al, 2003;Izumi et al, 2003;Ahmadian et al, 2004) formation in the Alzheimer's disease brain. Under physiological conditions, activation of insulin receptor inhibits glycogen synthase kinase-3b (GSK3b) activity via a chain of intracellular reactions including activation of PI-3-K, formation of phosphatidylinositol-3,4,5-trisphosphate (PtdIns 3,4,5 P 3 ), phosphoinositide-dependent protein kinase (PDK)-dependent phosphorylation and activation of Akt, and phosphorylation of GSK3b on serine-9.…”

Section: Discussionmentioning

confidence: 99%

Reduced insulin‐induced phosphatidylinositol‐3‐kinase activation in peripheral blood mononuclear leucocytes from patients with Alzheimer's disease

Castri¹,

Iacovelli

Blasi

et al. 2007

Eur J of Neuroscience

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The epidemiological finding of an increased risk of dementia in patients with diabetes mellitus has raised the hypothesis that a dysfunction of the insulin receptors plays a role in the pathogenesis of Alzheimer's disease (AD). A possible link is suggested by the evidence that the insulin-stimulated phosphatidylinositol-3-kinase (PI-3-K)/phospho-Akt pathway negatively controls the glycogen synthase kinase-3beta. The activation of this enzyme mediates the hyperphosphorylation of the tau protein, a relevant step in the formation of the neurofibrillary tangles associated with AD. We hypothesized that the neurodegeneration associated with AD is related to an impairment of the intracellular signalling stimulated by insulin receptors. To test this hypothesis we assessed the PI-3-K/phospho-Akt pathway following in-vitro challenge with insulin in peripheral blood mononuclear cells from subjects with AD (n = 20) and controls (n = 20). We found that the stimulation of PI-3-K is blunted in patients with AD with respect to control. The reduction did not correlate with the extent of cognitive decline or with scores at neuropsychological tests exploring attention, memory, language or visuospatial abilities. The study supports the hypothesis that an impaired control of glycogen synthase kinase-3beta activity by insulin receptor-mediated signalling plays a role in the pathogenesis of AD, facilitating tau protein phosphorylation and neurofibrillary tangle formation.

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“…Rats were killed on postnatal d 28 -32 for transverse hippocampal slice preparation and recording (22). After incubation slices were transferred to a submersion recording chamber continuously perfused with artificial cerebrospinal fluid containing (in millimolar): 124 NaCl, 5 KCl, 2 MgSO 4 , 2 CaCl 2 , 1.25 NaH 2 PO 4 , 22 NaHCO 3 , and 10 glucose, bubbled with 95% O 2 -5% CO 2 at 30°C.…”

Section: Methodsmentioning

confidence: 99%

Repetitive Hypoglycemia in Young Rats Impairs Hippocampal Long-Term Potentiation

et al. 2004

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Mechanisms underlying cognitive dysfunction in young diabetic children are poorly understood, and may include synaptic dysfunction from insulin-induced hypoglycemia. We developed a model of repetitive insulin-induced hypoglycemia in young rats and examined hippocampal long-term potentiation, an electrophysiologic assay of synaptic plasticity, 3-5 d after the last hypoglycemic event. Three hypoglycemic events between postnatal d 21-25 produced modest cortical (17 Ϯ 2.9 dead neurons per section in parasagittal cortex), but not hippocampal, neuron death quantified by Fluoro-Jade B staining. There was no change in neurogenesis in the hippocampal dentate granule cell region by quantification of bromodeoxyuridine incorporation. Although normal baseline hippocampal synaptic responses were elicited from hippocampal slices from hypoglycemic animals, long-term synaptic potentiation could not be induced in hippocampal slices from rats subjected to hypoglycemia. These results suggest that repetitive hypoglycemia in the developing brain can cause selective impairment of synaptic plasticity in the absence of cell death, and without complete disruption of basal synaptic transmission. We speculate that impaired synaptic plasticity in the hippocampus caused by repetitive hypoglycemia could underlie memory and cognitive deficits observed in young diabetic children, and that cortical neuron death caused by repetitive hypoglycemia in the developing brain may contribute to other neurologic, cognitive, and psychological problems sometimes encountered in diabetic children. (Pediatr Res 55: 372-379, 2004) Abbreviations LTP, long-term potentiation Hex, hexamethonium chloride HI, hexamethonium chloride plus insulin EPSP, excitatory postsynaptic potential BrdU, bromodeoxyuridine PBS؉, PBS with 10% goat serum and 0.3% Triton X DAPI, 4',6-diamidino-2-phenylindole Diabetic children diagnosed before age 5 y are at risk for lasting cognitive impairment (1), and hypoglycemia may be a causative factor (2, 3). Young children on conventional therapy are prone to hypoglycemic events (4 -8), which occur even more frequently on intensive therapy (9, 10). Severe hypoglycemia was a risk factor for cognitive deficits in one prospective study (11), but not another (12), raising the possibility that less severe, repetitive hypoglycemia (not evaluated in these studies) causes cognitive impairment. Moreover, continuous glucose monitoring reveals that prolonged nocturnal hypoglycemia occurs frequently in children with type 1 diabetes (13,14). The mechanisms by which diabetes or hypoglycemia produce relatively subtle cognitive deficits without overt brain injury are poorly understood, and these two factors are difficult to study independently in diabetic children. Therefore, we developed a model of hypoglycemia-induced brain injury in developing rats to simulate repetitive hypoglycemia as encountered in diabetic children to study the consequences of repetitive hypoglycemia at a cellular level under more controlled experimental conditions.

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Effects of insulin on long-term potentiation in hippocampal slices from diabetic rats

Cited by 54 publications

References 54 publications

Experimental Diabetes Attenuates Cerebral Cortical−Evoked Forelimb Motor Responses

Experimental Diabetes Attenuates Cerebral Cortical−Evoked Forelimb Motor Responses

Reduced insulin‐induced phosphatidylinositol‐3‐kinase activation in peripheral blood mononuclear leucocytes from patients with Alzheimer's disease

Repetitive Hypoglycemia in Young Rats Impairs Hippocampal Long-Term Potentiation

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