Apnea promotes glutamate-induced excitotoxicity in hippocampal neurons

Abstract

Patients with obstructive sleep apnea (OSA) exhibit hippocampal damage and cognitive deficits. To determine the effect of apnea on the synaptic transmission in the hippocampus, we performed electrophysiological studies in an in vivo guinea pig model of OSA. Specifically, we determined the cornu ammonis region 1 (CA1) field excitatory postsynaptic potential (fEPSP) response to cornu ammonis region 3 (CA3) stimulation and examined the presynaptic mechanisms underlying the changes in the fEPSP. Single episodes of apnea resulted in a maximal potentiation of the fEPSPs at 1 to 3 min after the termination of each episode of apnea. The mean amplitude and slope of the post-apneic fEPSP was significantly larger compared with the pre-apneic control. These changes were accompanied by a significant decrease in the paired-pulse facilitation ratio during the post-apneic period compared with the pre-apneic control. The N-methyl-D-aspartate (NMDA) glutamate receptor antagonist MK-801, when applied locally to the CA1 recording site by pressure ejection, blocked the apnea-induced potentiation of the fEPSP. In the experimental animals that were subjected to extended periods of recurrent apnea, CA1 neurons exhibited positive immunoreactivity for fragmented DNA strands, which indicates apoptotic cell death. The present results demonstrate that apnea-induced potentiation of the hippocampal CA1 fEPSP is mediated by an NMDA receptor mechanism. We therefore conclude that recurrent apnea produces abnormally high levels of glutamate that results in the apoptosis of CA1 neurons. We hypothesize that this damage is reflected by the cognitive deficits that are commonly observed in patients with breathing disorders such as OSA.

Obstructive sleep apnea is associated with altered midbrain chemical concentrations

“…Given the lower NAA, the higher glutamate levels could reflect greater astrocyte activation (Kimelberg et al, 1990; Szatkowski et al, 1990), perhaps as a compensatory mechanism attempting to correct for lower neural activity. In addition to altering function, high levels of extracellular glutamate lead to excitotoxicity and in apoptosis of neurons (Fung et al, 2007). Hence, high glutamate is consistent with low NAA if the latter is considered a marker of neuronal cells (as opposed to neuronal function).…”

Chronic intermittent hypoxia-induced deficits in synaptic plasticity and neurocognitive functions: a role for brain-derived neurotrophic factor

“…For example, FUNG et al [33] suggested that intermittent hypoxia produces abnormally high level of glutamate and causes excitotoxicity in hippocampal neurons. LI et al [34] concluded from their study that intermittent hypoxia in the rat is associated with an increased expression of iNOS which may play a critical role in IH-mediated neurobehavioural deficits.…”

Propofol attenuates intermittent hypoxia induced up-regulation of proinflammatory cytokines in microglia through inhibiting the activation of NF-Bκ/p38 MAPK signalling

“…Intermittent hypoxia (IH), one of the pathophysiologic changes resulting from obstructions of the upper airway during sleep, may play a key role in the structural neuron damage in the CNS, especially excitotoxicity in hippocampal neurons [8,9,36]. Moreover, IH would lead to the up-regulation of ROS, NO, and downstream pro-inflammatory responses [2,30].…”