Remote and Persistent Alterations in Glutamate Receptor Subunit Composition Induced by Spreading Depolarizations in Rat
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BRIEF COMMUNICATION
Remote and Persistent Alterations in Glutamate Receptor Subunit Composition Induced by Spreading Depolarizations in Rat Brain Kinsey A. Barhorst1 · Yara Alfawares2 · Jennifer L. McGuire3 · Steve C. Danzer4,5,6,7 · Jed A. Hartings3,8 · Laura B. Ngwenya3,8,9 Received: 13 May 2020 / Accepted: 6 November 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Spreading depolarizations (SDs) are massive breakdowns of ion homeostasis in the brain’s gray matter and are a necessary pathologic mechanism for lesion development in various injury models. However, injury-induced SDs also propagate into remote, healthy tissue where they do not cause cell death, yet their functional long-term effects are unknown. Here we induced SDs in uninjured cortex and hippocampus of Sprague–Dawley rats to study their impact on glutamate receptor subunit expression after three days. We find that both cortical and hippocampal tissue exhibit changes in glutamate receptor subunit expression, including GluA1 and GluN2B, suggesting that SDs in healthy brain tissue may have a role in plasticity. This study is the first to show prolonged effects of SDs on glutamate signaling and has implications for neuroprotection strategies aimed at SD suppression. Keywords Spreading depolarization · Spreading depression · Glutamate receptor · Plasticity · Brain injury
Introduction
Kinsey A. Barhorst and Yara Alfawares have contributed equally. * Laura B. Ngwenya [email protected] 1
University of Cincinnati, College of Medicine, Cincinnati, OH, USA
2
University of Cincinnati, Cincinnati, OH, USA
3
University of Cincinnati, Department of Neurosurgery, 231 Albert Sabin Way, MSB 5251, Cincinnati, OH 45267, USA
4
Cincinnati Children’s Hospital Medical Center, Department of Anesthesia, Cincinnati, OH, USA
5
University of Cincinnati, Department of Anesthesia, Cincinnati, OH, USA
6
Cincinnati Children’s Hospital Medical Center, Center for Pediatric Neuroscience, Cincinnati, OH, USA
7
University of Cincinnati, Department of Pediatrics, Cincinnati, OH, USA
8
University of Cincinnati, Collaborative for Research on Acute Neurological Injury (CRANI), Cincinnati, OH, USA
9
University of Cincinnati, Department of Neurology and Rehabilitation Medicine, Cincinnati, OH, USA
Spreading depolarizations (SD) are massive breakdowns in neuronal membrane ion gradients that propagate through contiguous gray matter at 2–9 mm/min, causing cellular edema and silencing of electrical activity. These pathologic waves occur spontaneously in brain injury (Lauritzen and Strong 2017; Lauritzen et al. 2011), have a causal role in lesion development, and worsen tissue outcome (Hartings et al. 2017b; von Bornstadt et al. 2015). However, SDs also propagate from injury foci into surrounding normal tissue where their impact may be benign (Nedergaard and Hansen 1988), or where they could contribute to neuroplasticity and long-term functional changes (Shuttleworth et al. 2019). These long-term consequences of SDs in remot
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