van der Heide LP, Kamal A, Artola A, Gispen WH, Ramakers GM. Insulin modulates hippocampal activity-dependent synaptic plasticity in a N-methyl-D-aspartate receptor and phosphatidylinositol-3-kinase-dependent manner. J Neurochem 94: 1158-1166
Insulin and its receptor are both present in the central nervous system and are implicated in neuronal survival and hippocampal synaptic plasticity. Here we show that insulin activates phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB), and results in an induction of long-term depression (LTD) in hippocampal CA1 neurones. Evaluation of the frequency-response curve of synaptic plasticity revealed that insulin induced LTD at 0.033 Hz and LTP at 10 Hz, whereas in the absence of insulin, 1 Hz induced LTD and 100 Hz induced LTP. LTD induction in the presence of insulin required low frequency synaptic stimulation (0.033 Hz) and blockade of GABAergic transmission. The LTD or LTP induced in the presence of insulin was N-methyl-d-aspartate (NMDA) receptor specific as it could be inhibited by alpha-amino-5-phosphonopentanoic acid (APV), a specific NMDA receptor antagonist. LTD induction was also facilitated by lowering the extracellular Mg(2+) concentration, indicating an involvement of NMDA receptors. Inhibition of PI3K signalling or discontinuing synaptic stimulation also prevented this LTD. These results show that insulin modulates activity-dependent synaptic plasticity, which requires activation of NMDA receptors and the PI3K pathway. The results obtained provide a mechanistic link between insulin and synaptic plasticity, and explain how insulin functions as a neuromodulator.
"Insulin dysregulation contributes to AD pathologies by reducing brain glucose utilization.57,58,59 Insulin affects neuronal cognition and memory by regulating ion channels and neurotransmitter receptors in AD brains.60,61 Considering that insulin signal transduction is important for cognitive function,59,62,63,64 our data indicated that Agm could induce the activation of brain insulin signal transduction and improve learning and cognitive decline in STZ-induced Alzheimer rat model. "
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) results in memory impairment and neuronal cell death in the brain. Previous studies demonstrated that intracerebroventricular administration of streptozotocin (STZ) induces pathological and behavioral alterations similar to those observed in AD. Agmatine (Agm) has been shown to exert neuroprotective effects in central nervous system disorders. In this study, we investigated whether Agm treatment could attenuate apoptosis and improve cognitive decline in a STZ-induced Alzheimer rat model.
We studied the effect of Agm on AD pathology using a STZ-induced Alzheimer rat model. For each experiment, rats were given anesthesia (chloral hydrate 300 mg/kg, ip), followed by a single injection of STZ (1.5 mg/kg) bilaterally into each lateral ventricle (5 μL/ventricle). Rats were injected with Agm (100 mg/kg) daily up to two weeks from the surgery day.
Agm suppressed the accumulation of amyloid beta and enhanced insulin signal transduction in STZ-induced Alzheimer rats [experimetal control (EC) group]. Upon evaluation of cognitive function by Morris water maze testing, significant improvement of learning and memory dysfunction in the STZ-Agm group was observed compared with the EC group. Western blot results revealed significant attenuation of the protein expressions of cleaved caspase-3 and Bax, as well as increases in the protein expressions of Bcl2, PI3K, Nrf2, and γ-glutamyl cysteine synthetase, in the STZ-Agm group.
Our results showed that Agm is involved in the activation of antioxidant signaling pathways and activation of insulin signal transduction. Accordingly, Agm may be a promising therapeutic agent for improving cognitive decline and attenuating apoptosis in AD.
Yonsei medical journal 05/2014; 55(3):689-99. DOI:10.3349/ymj.2014.55.3.689 · 1.29 Impact Factor
"In brain, insulin contributes to memory function through regulation of neurotransmitter receptors and synaptic function  . Additionally, insulin signal transduction also promotes neurite outgrowth and axonal regeneration in the brain   . "
[Show abstract][Hide abstract] ABSTRACT: Vascular dementia is caused by various factors, including increased age, diabetes, hypertension, atherosclerosis, and stroke. Adiponectin is an adipokine secreted by adipose tissue. Adiponectin is widely known as a regulating factor related to cardiovascular disease and diabetes. Adiponectin plasma levels decrease with age. Decreased adiponectin increases the risk of cardiovascular disease and diabetes. Adiponectin improves hypertension and atherosclerosis by acting as a vasodilator and antiatherogenic factor. Moreover, adiponectin is involved in cognitive dysfunction via modulation of insulin signal transduction in the brain. Case-control studies demonstrate the association between low adiponectin and increased risk of stroke, hypertension, and diabetes. This review summarizes the recent findings on the association between risk factors for vascular dementia and adiponectin. To emphasize this relationship, we will discuss the importance of research regarding the role of adiponectin in vascular dementia.
BioMed Research International 04/2014; 2014(6):261672. DOI:10.1155/2014/261672 · 3.17 Impact Factor
"Insulin receptors are highly enriched in synaptosomes (Werther et al., 1989), have been co-localized with axon terminal markers synaptophysin and synapsin 1 (Mielke et al., 2006) and are found in post-synaptic density (PSD) fractions where they may interact with scaffolding protein shank and PSD-95 via the insulin receptor tyrosine kinase substrate IRSp53 (Abbott et al., 1999; Bockmann et al., 2002). Insulin enhances neurite outgrowth, modulates catecholamine release and uptake, regulates trafficking of ligand-gated ion channels, regulates expression and localization of GABA, NMDA, and AMPA receptors , modulates activity dependent synaptic plasticity via NMDA and PI3K-Akt (van der Heide et al., 2005), and plays a critical role in the development and maintenance of excitatory synapses (Chiu et al., 2008). There have been relatively few attempts to investigate how genetic or diet-induced insulin resistance affects cognition-related circuitry and neurotransmission in animal models. "
[Show abstract][Hide abstract] ABSTRACT: Insulin resistance and other features of the metabolic syndrome are increasingly recognized for their effects on cognitive health. To ascertain mechanisms by which this occurs, we fed mice a very high fat diet (60% kcal by fat) for 17days or a moderate high fat diet (HFD, 45% kcal by fat) for 8weeks and examined changes in brain insulin signaling responses, hippocampal synaptodendritic protein expression, and spatial working memory. Compared to normal control diet mice, cerebral cortex tissues of HFD mice were insulin-resistant as evidenced by failed activation of Akt, S6 and GSK3β with ex-vivo insulin stimulation. Importantly, we found that expression of brain IPMK, which is necessary for mTOR/Akt signaling, remained decreased in HFD mice upon activation of AMPK. HFD mouse hippocampus exhibited increased expression of serine-phosphorylated insulin receptor substrate 1 (IRS1-pS(616)), a marker of insulin resistance, as well as decreased expression of PSD-95, a scaffolding protein enriched in post-synaptic densities, and synaptopodin, an actin-associated protein enriched in spine apparatuses. Spatial working memory was impaired as assessed by decreased spontaneous alternation in a T-maze. These findings indicate that HFD is associated with telencephalic insulin resistance and deleterious effects on synaptic integrity and cognitive behaviors.
Neurobiology of Disease 03/2014; 67. DOI:10.1016/j.nbd.2014.03.011 · 5.08 Impact Factor
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