Effects of prolyl-hydroxylase inhibition and chronic intermittent hypoxia on synaptic transmission and plasticity in the rat CA1 and dentate gyrus

Abstract

Publication informationNeurobiology of Disease, 62 (February 2014): 8-17 Publisher Elsevier Item record/more information http://hdl.handle.net/10197/4791 Publisher's statementThis is the author's version of a work that was accepted for publication in Neurobiology of Disease. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Neurobiology of Disease (In press (2013) AbstractChronic intermittent hypoxia (CIH) is an underlying component of obstructive sleep apnoea and has been shown to have deleterious and damaging effects on central neurons and to impair synaptic plasticity in the CA1 region of the rat hippocampus. CIH has previously been shown to impair synaptic plasticity and working memory. CIH is a potent inducer of hypoxia inducible factor (HIF), a key regulator in a cell's adaptation to hypoxia that plays an important role in the fate of neurons during ischemia. Levels of HIF-1α are regulated by the activity of a group of enzymes called HIF-prolyl 4-hydroxylases (PHDs) and these have become potential pharmalogical targets for preconditioning against ischemia. However little is known about the effects of prolyl hydroxylase inhibition and CIH on synaptic transmission and plasticity in sub-regions of the hippocampus. Male Wistar rats were treated for 7-days with either saline, CIH or PHD inhibition (dimethyloxaloylglycine, DMOG; 50mg/kg, i.p.). At the end of treatment all three groups showed no change in synaptic excitability using paired pulse paradigms. However long-term potentiation (LTP) was impaired in the CA1 region of the hippocampus in both CIH and DMOG treated animals. LTP induced in the dentate gyrus was not significantly affected by either CIH or DMOG treatment. We also investigated the effect of 7-day CIH and DMOG treatment on the recovery of synaptic transmission following an acute 30 min hypoxic insult. CIH treated animals showed an improved rate of recovery of synaptic transmission following re-oxygenation in both the CA1 and dentate gyrus. These results suggest that LTP induction in the CA1 region is more sensitive to both CIH and DMOG treatment than the dentate gyrus.

Critical Role of Endoplasmic Reticulum Stress in Chronic Intermittent Hypoxia-Induced Deficits in Synaptic Plasticity and Long-Term Memory

“…We and other investigators had previously demonstrated that hippocampal long-term synaptic plasticity is impaired after 7-14 days of IH treatments (60,63), a phenomenon that may underlie memory impairment in OSA subjects. To test whether ER stress plays a direct role in this process, we performed two sets of experiments.…”

A role for Hypoxia Inducible Factor 1a (HIF1a) in intermittent hypoxia-dependent changes to spatial memory and synaptic plasticity

“…Employing pharmacological means or IH to enhance HIF1a in the hippocampus correlated with the 294 suppression of LTP in area CA1 (Wall et al, 2014). Similarly, oxidative stress has been implicated as a 295 significant factor that could influence neurophysiological and behavioral outcomes in response to IH (Xu et al, 296 2004).…”

Intermittent Hypoxia Disrupts Adult Neurogenesis and Synaptic Plasticity in the Dentate Gyrus

“…These impairments include learning and memory deficits (Jackson et al, 2011), difficulties in attention (Beebe and Gozal, 2002), and emotional dysregulation (Schröder and O'Hara, 2005). Although neuroimaging studies suggest that multiple brain regions are impacted by sleep apnea, the hippocampal formation is frequently identified as a site of injury in this condition (Morrell et al, 2003;Castronovo et al, 2009;Canessa et al, 2011;Torelli et al, 2011;Cha et al, 2017).…”