Effects of Prolyl-Hydroxylase Inhibition and Chronic Intermittent Hypoxia on Synaptic Transmission and Plasticity in the Rat CA1 and Dentate Gyrus

Neurobiol Dis. 2014 Feb;62:8-17. doi: 10.1016/j.nbd.2013.08.016. Epub 2013 Sep 17.

Abstract

Chronic 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 pharmacological 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 30min hypoxic insult. CIH treated animals showed an improved rate of recovery of synaptic transmission following re-oxygenation in both the CA1 and the dentate gyrus. These results suggest that LTP induction in the CA1 region is more sensitive to both CIH and DMOG treatments than the dentate gyrus.

Keywords: 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid; AMP-activated protein kinase; AMPA; AMPK; BDNF; CA1; CIH; CREB; Chronic intermittent hypoxia (CIH); Cornu ammons 1 (CA1); DMOG; DMSO; Dentate gyrus (dentate gyrus); Dimethyloxaloylglycine (DMOG); EPO; HFS; HIF; Hypoxia inducible factor 1 alpha; LTP; Long term potentiation (LTP); MCAO; OSA; PDE4D; PHD; Prolyl hydroxylase domain (PHD); ROS; aCSF; artificial cerebrospinal fluid; brain derived neurotrophic factor; cAMP; cAMP response element-binding protein; chronic intermittent hypoxia; cornu ammonis 1; cyclic adenosine monophosphate; dimethyl sulfoxide; dimethyloxaloylglycine; erythropoietin; fEPSP; field excitatory postsynaptic potential; high frequency stimulation; hypoxia inducible factor; long-term potentiation; middle cerebral artery occlusion; obstrutive sleep apnoea; phosphodiesterase 4D; prolyl hydroxylase domain; reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids, Dicarboxylic / pharmacology*
  • Animals
  • CA1 Region, Hippocampal / drug effects
  • CA1 Region, Hippocampal / physiopathology
  • CREB-Binding Protein / metabolism
  • Dentate Gyrus / drug effects
  • Dentate Gyrus / physiopathology
  • Erythropoietin / metabolism
  • Hematocrit
  • Hippocampus / drug effects*
  • Hippocampus / physiopathology*
  • Hypoxia, Brain / physiopathology*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors*
  • Male
  • Neuronal Plasticity / drug effects*
  • Rats
  • Rats, Wistar
  • Synaptic Transmission / drug effects*

Substances

  • Amino Acids, Dicarboxylic
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Erythropoietin
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • CREB-Binding Protein
  • Crebbp protein, rat
  • oxalylglycine