A role for prolyl hydroxylase domain proteins in hippocampal synaptic plasticity

Abstract

Hypoxia-inducible factors (HIFs) are key transcriptional regulators that play a major role in oxygen homeostasis. HIF activity is tightly regulated by oxygen-dependent hydroxylases, which additionally require iron and 2-oxoglutarate as cofactors. Inhibition of these enzymes has become a novel target to modulate the hypoxic response for therapeutic benefit. Inhibition of prolyl-4-hydroxylase domains (PHDs) have been shown to delay neuronal cell death and protect against ischemic injury in the hippocampus. In this study we have examined the effects of prolyl hydroxylase inhibition on synaptic transmission and plasticity in the hippocampus. Field excitatory postsynaptic potentials (fEPSPs) and excitatory postsynaptic currents (EPSCs) were elicited by stimulation of the Schaffer collateral pathway in the CA1 region of the hippocampus. Treatment of rat hippocampal slices with low concentrations (10 µM) of the iron chelator deferosoxamine (DFO) or the 2-oxoglutarate analogue dimethyloxalyl glycine (DMOG) had no effect on fEPSP. In contrast, application of 1 mM DMOG resulted in a significant decrease in fEPSP slope. Antagonism of the NMDA receptor attenuated the effects of DMOG on baseline synaptic signalling. In rat hippocampal slices pretreated with DMOG and DFO the induction of longterm potentiation (LTP) by tetanic stimulation was strongly impaired. Similarly, neuronal knockout of the single PHD family member PHD2 prevented murine hippocampal LTP. Pre-conditioning of PHD2 deficient hippocampi with either DMOG, DFO or the PHD specific inhibitor JNJ-42041935, did not further decrease LTP suggesting that DMOG and DFO influences synaptic plasticity primarily by inhibiting PHDs rather than unspecific effects. These findings provide striking evidence for a modulatory role of PHD proteins on synaptic plasticity in the hippocampus.

Dissecting the role of redox signaling in neuronal development

“…Moreover, genetic models specific for inactivation of the prolyl hydroxylase domain 2 enzyme exhibit similar deficits in LTP, which cannot be exacerbated by the use of deferoxamine or dimethyloxalyl glycine (Corcoran et al . ). These findings suggest that activation of prolyl hydroxylase domain 2 by iron underlies its observed effects in promoting LTP (Fig.…”

Oxygen sensors and neuronal adaptation to ischemia

“…We previously showed that application of PHD inhibitors or neuron-specific deletion of PHD2 significantly decreased excitatory postsynaptic potentials and strongly impaired the induction of long-term potentiation [6]. Recently, Segura et al confirmed our hypothesis that PHDs might control neuronal adaptation to hypoxia/ischemia at the level of synaptic activity [7].…”

Hypoxia‐inducible factor signalling mechanisms in the central nervous system

“…, Corcoran et al . ). The effects of iron chelation via application of DFO are even greater, decreasing transmission by approx.…”

“…Preliminary work from our laboratory suggests acute and chronic inhibition of PHDs by dimethyloxalyl glycine (DMOG), and DFO impairs synaptic plasticity (long‐term potentiation) in the rat and mouse hippocampus (Corcoran et al . ).…”