Anesthesia and post‐mortem interval profoundly influence the regulatory serine phosphorylation of glycogen synthase kinase‐3 in mouse brain

Li, Xiaohua; Friedman, Ari B; Roh, Meejeon; Jope, Richard S.

doi:10.1111/j.1471-4159.2004.02898.x

Cited by 58 publications

(44 citation statements)

References 21 publications

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“…Consistent with our results (Fig. 5B), Li et al (2005) show that anesthesia enhances the inhibitory phosphorylation of GSK-3␤. This enhanced GSK-3␤ Ser9 phosphorylation is seen in all animal models undergoing hypothermia (Okawa et al, 2003;Planel et al, 2004) and is probably mediated through the inhibition of PP1 and/or PP2A at low temperatures.…”

Section: Discussionsupporting

confidence: 82%

Anesthesia Leads to Tau Hyperphosphorylation through Inhibition of Phosphatase Activity by Hypothermia

Planel¹,

Richter²,

Nolan³

et al. 2007

J. Neurosci.

341

327

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Postoperative cognitive dysfunction, confusion, and delirium are common after general anesthesia in the elderly, with symptoms persisting for months or years in some patients. Even middle-aged patients are likely to have postoperative cognitive dysfunction for months after surgery, and Alzheimer's disease (AD) patients appear to be particularly at risk of deterioration after anesthesia. Several investigators have thus examined whether general anesthesia is associated with AD, with some studies suggesting that exposure to anesthetics may increase the risk of AD. However, little is known on the biochemical consequences of anesthesia on pathogenic pathways in vivo. Here, we investigated the effect of anesthesia on tau phosphorylation and amyloid precursor protein (APP) metabolism in mouse brain. We found that, regardless of the anesthetic used, anesthesia induced rapid and massive hyperphosphorylation of tau, rapid and prolonged hypothermia, inhibition of Ser/Thr PP2A (protein phosphatase 2A), but no changes in APP metabolism or A␤ (␤-amyloid peptide) accumulation. Reestablishing normothermia during anesthesia completely rescued tau phosphorylation to normal levels. Our results indicate that changes in tau phosphorylation were not a result of anesthesia per se, but a consequence of anesthesia-induced hypothermia, which led to inhibition of phosphatase activity and subsequent hyperphosphorylation of tau. These findings call for careful monitoring of core temperature during anesthesia in laboratory animals to avoid artifactual elevation of protein phosphorylation. Furthermore, a thorough examination of the effect of anesthesia-induced hypothermia on the risk and progression of AD is warranted.

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Section: Discussionsupporting

confidence: 82%

Anesthesia Leads to Tau Hyperphosphorylation through Inhibition of Phosphatase Activity by Hypothermia

Planel¹,

Richter²,

Nolan³

et al. 2007

J. Neurosci.

341

327

View full text Add to dashboard Cite

show abstract

“…Postmortem variables such as PMI may also impact phosphorylation (Funk et al, 2012;Li et al, 1996Li et al, , 2003Li et al, , 2005O'Callaghan and Sriram, 2004;Oka et al, 2011). The often transient nature of phosphorylation is well characterized, and in part led to the development of strategies (such as microwave devices) for rapid 'fixation' of brain tissues particularly for proteins with a rapid turnover cycle for phosphorylation/dephosphorylation (O'Callaghan and Sriram, 2004).…”

Section: Biochemical Assessment Of Post-translational Modification Inmentioning

confidence: 99%

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

Neuropsychopharmacol

106

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We propose that postmortem tissue is an underutilized substrate that may be used to translate genetic and/or preclinical studies, particularly for neuropsychiatric illnesses with complex etiologies. Postmortem brain tissues from subjects with schizophrenia have been extensively studied, and thus serve as a useful vehicle for illustrating the challenges associated with this biological substrate. Schizophrenia is likely caused by a combination of genetic risk and environmental factors that combine to create a disease phenotype that is typically not apparent until late adolescence. The complexity of this illness creates challenges for hypothesis testing aimed at understanding the pathophysiology of the illness, as postmortem brain tissues collected from individuals with schizophrenia reflect neuroplastic changes from a lifetime of severe mental illness, as well as treatment with antipsychotic medications. While there are significant challenges with studying postmortem brain, such as the postmortem interval, it confers a translational element that is difficult to recapitulate in animal models. On the other hand, data derived from animal models typically provide specific mechanistic and behavioral measures that cannot be generated using human subjects. Convergence of these two approaches has led to important insights for understanding molecular deficits and their causes in this illness. In this review, we discuss the problem of schizophrenia, review the common challenges related to postmortem studies, discuss the application of biochemical approaches to this substrate, and present examples of postmortem schizophrenia studies that illustrate the role of the postmortem approach for generating important new leads for understanding the pathophysiology of severe mental illness.

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“…Unfortunately, this cannot be addressed using postmortem human brain samples because GSK3β is rapidly dephosphorylated following death (Li et al 2005). Therefore, in this study we examined whether in vitro and therapeutic in vivo lithium treatment increased the serine9-phosphorylation of GSK3β in human peripheral blood mononuclear cells (PBMCs).…”

mentioning

confidence: 99%

Lithium Regulates Glycogen Synthase Kinase-3β in Human Peripheral Blood Mononuclear Cells: Implication in the Treatment of Bipolar Disorder

Friedman

Zhu

et al. 2007

Biological Psychiatry

Self Cite

106

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Background-Bipolar disorder has been linked to alterations in the multifunctional enzyme glycogen synthase kinase-3β (GSK3β). The mood stabilizer lithium inhibits GSK3β in vitro and in mouse brain, and this is currently the strongest known potential therapeutic target of lithium. We tested whether lithium modified GSK3β in vivo or in vitro in peripheral blood mononuclear cells (PBMCs) from healthy control and bipolar disorder subjects.

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Anesthesia and post‐mortem interval profoundly influence the regulatory serine phosphorylation of glycogen synthase kinase‐3 in mouse brain

Cited by 58 publications

References 21 publications

Anesthesia Leads to Tau Hyperphosphorylation through Inhibition of Phosphatase Activity by Hypothermia

Anesthesia Leads to Tau Hyperphosphorylation through Inhibition of Phosphatase Activity by Hypothermia

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

Lithium Regulates Glycogen Synthase Kinase-3β in Human Peripheral Blood Mononuclear Cells: Implication in the Treatment of Bipolar Disorder

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