The Effects of Hypoxia and Inflammation on Synaptic Signaling in the CNS

Abstract

Normal brain function is highly dependent on oxygen and nutrient supply and when the demand for oxygen exceeds its supply, hypoxia is induced. Acute episodes of hypoxia may cause a depression in synaptic activity in many brain regions, whilst prolonged exposure to hypoxia leads to neuronal cell loss and death. Acute inadequate oxygen supply may cause anaerobic metabolism and increased respiration in an attempt to increase oxygen intake whilst chronic hypoxia may give rise to angiogenesis and erythropoiesis in order to promote oxygen delivery to peripheral tissues. The effects of hypoxia on neuronal tissue are exacerbated by the release of many inflammatory agents from glia and neuronal cells. Cytokines, such as TNF-α, and IL-1β are known to be released during the early stages of hypoxia, causing either local or systemic inflammation, which can result in cell death. Another growing body of evidence suggests that inflammation can result in neuroprotection, such as preconditioning to cerebral ischemia, causing ischemic tolerance. In the following review we discuss the effects of acute and chronic hypoxia and the release of pro-inflammatory cytokines on synaptic transmission and plasticity in the central nervous system. Specifically we discuss the effects of the pro-inflammatory agent TNF-α during a hypoxic event.

Keywords: HIF-1α; TNF-α; adenosine; hippocampus; hypoxia; long-term potentiation; prolyl hydroxylase inhibitor.

Figure 1

The effects of hypoxia on adenosine release in the CNS. Hypoxia causes a breakdown of extracellular ATP and AMP along with activation of membrane-bound transporters such as ectonucleotidases, leading to a build-up of extracellular adenosine. Adenosine binds presynaptically to A₁Rs attenuating voltage dependent calcium channel (VDCC) function and thus neurotransmitter release and also binds postsynaptically to A₁Rs receptors inactivating glutamatergic NMDARs. Adenosine is released from astrocytes in response to chronic hypoxia.

Figure 2

Hypoxia and NFκB activation. During hypoxic HIF-1α binding to the HRE induces the expression of NFκB (left). NFκB p50 p65 dimer is able to freely activate the transcription of inflammatory and HIF proteins (right).

Figure 3

Putative signaling pathways activated after HFS- and TBS-induced LTP. HFS-induced LTP may be dependent on the breakdown of 5′ AMP into adenosine. Adenosine activates the A_2AR receptor leading to cAMP and PKA activation. TBS-induced LTP involves the influx of Ca²⁺ and subsequent activation of calpain-1. The activation of calpain-1 leads to a calapin-1-mediated suprachiasmatic nucleus circadian oscillatory protein degradation and ERK activation. Exogenous TNF-α inhibits LTP induced by TBS only. During hypoxia, TNF-α may have potentiating effect on HFS-induced LTP but not TBS.