Chronic neuronal activation leads to elevated lactate dehydrogenase A through the AMP-activated protein kinase/hypoxia-inducible factor-1α hypoxia pathway

Author:

Ksendzovsky Alexander123,Bachani Muznabanu4,Altshuler Marcelle2,Walbridge Stuart2,Mortazavi Armin2,Moyer Mitchell1,Chen Chixiang1ORCID,Fayed Islam2ORCID,Steiner Joseph3,Edwards Nancy2,Inati Sara K5,Jahanipour Jahandar6ORCID,Maric Dragan6,Heiss John D2,Kapur Jaideep78,Zaghloul Kareem A2ORCID

Affiliation:

1. Department of Neurosurgery, School of Medicine, University of Maryland , Baltimore, MD 21201 , USA

2. Surgical Neurology Branch, National Institute of Neurologic Disorders and Stroke, National Institute of Health , Bethesda, MD 20892 , USA

3. Department of Neurological Surgery, University of Virginia Health System, University of Virginia , Charlottesville, VA 22903 , USA

4. Drug Development Unit, National Institute of Neurologic Disorders and Stroke, National Institute of Health , Bethesda, MD 20892 , USA

5. Office of the Clinical Director, National Institute of Neurologic Disorders and Stroke, National Institute of Health , Bethesda, MD 20892 , USA

6. Flow and Cytometry Core, National Institute of Neurologic Disorders and Stroke, National Institute of Health , Bethesda MD, 20892 , USA

7. Department of Neurology, University of Virginia Health System, University of Virginia , Charlottesville, VA 22903 , USA

8. Neuroscience Department, University of Virginia Health System, University of Virginia , Charlottesville, VA 22903 , USA

Abstract

Abstract Recent studies suggest that changes in neuronal metabolism are associated with epilepsy. High rates of ATP depletion, lactate dehydrogenase A and lactate production have all been found in epilepsy patients, animal and tissue culture models. As such, it can be hypothesized that chronic seizures lead to continuing elevations in neuronal energy demand which may lead to an adapted metabolic response and elevations of lactate dehydrogenase A. In this study, we examine elevations in the lactate dehydrogenase A protein as a long-term cellular adaptation to elevated metabolic demand from chronic neuronal activation. We investigate this cellular adaptation in human tissue samples and explore the mechanisms of lactate dehydrogenase A upregulation using cultured neurones treated with low Mg2+, a manipulation that leads to NMDA-mediated neuronal activation. We demonstrate that human epileptic tissue preferentially upregulates neuronal lactate dehydrogenase A, and that in neuronal cultures chronic and repeated elevations in neural activity lead to upregulation of neuronal lactate dehydrogenase A. Similar to states of hypoxia, this metabolic change occurs through the AMP-activated protein kinase/hypoxia-inducible factor-1α pathway. Our data therefore reveal a novel long-term bioenergetic adaptation that occurs in chronically activated neurones and provide a basis for understanding the interplay between metabolism and neural activity during epilepsy.

Funder

National Institute for Neurological Disorders and Stroke

Publisher

Oxford University Press (OUP)

Subject

Neurology,Cellular and Molecular Neuroscience,Biological Psychiatry,Psychiatry and Mental health

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