Mild systemic inflammation and moderate hypoxia transiently alter neuronal excitability in mouse somatosensory cortex

Abstract

During the perinatal period, the brain is highly vulnerable to hypoxia and inflammation, which often cause white matter injury and long-term neuronal dysfunction such as motor and cognitive deficits or epileptic seizures. We studied the effects of moderate hypoxia (HYPO), mild systemic inflammation (INFL), or the combination of both (HYPO+INFL) in mouse somatosensory cortex induced during the first postnatal week on network activity and compared it to activity in SHAM control animals. By performing in vitro electrophysiological recordings with multi-electrode arrays from slices prepared directly after injury (P8–10), one week after injury (P13–16), or in young adults (P28–30), we investigated how the neocortical network developed following these insults. No significant difference was observed between the four groups in an extracellular solution close to physiological conditions. In extracellular 8 mM potassium solution, slices from the HYPO, INFL, and HYPO+INFL group were more excitable than SHAM at P8–10 and P13–16. In these two age groups, the number and frequency of spontaneous epileptiform events were significantly increased compared to SHAM. The frequency of epileptiform events was significantly reduced by the NMDA antagonist D-APV in HYPO, INFL, and HYPO+INFL, but not in SHAM, indicating a contribution of NMDA receptors to this pathophysiological activity. In addition, the AMPA/kainate receptor antagonist CNQX suppressed the remaining epileptiform activity. Electrical stimulation evoked prominent epileptiform activity in slices from HYPO, INFL and HYPO+INFL animals. Stimulation threshold to elicit epileptiform events was lower in these groups than in SHAM. Evoked events spread over larger areas and lasted longer in treated animals than in SHAM. In addition, the evoked epileptiform activity was reduced in the older (P28–30) group indicating that cortical dysfunction induced by hypoxia and inflammation was transient and compensated during early development.

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

“…In rodent models, EEG studies are less common, due to the size of the post-natal brain. Using ex vivo multi-electrode arrays, Mordel et al (190) showed that inflammation and hypoxia, alone or together, increased the excitability of cortical neurons, in a glutamate receptor dependent manner. Interestingly, this research group has also shown that inflammation-induced alterations in cortical neuron spontaneous burst activity subsequently results in an increase in apoptosis in the same cell population (191).…”

Modulation of Neocortical Development by Early Neuronal Activity: Physiology and Pathophysiology

“…While it is obvious that hypoxic-ischemic periods and/or severe infections impair the development of the cortex by many mechanisms, e.g., by excitotoxicity or apoptosis (Vannucci, 2000 ), recent experiments suggest that direct and persistent effects of neonatal encephalopathy on neuronal activity may be also considered as potential factors leading to neonatal encephalopathy. A variety of studies demonstrated that hypoxic and/or ischemic conditions in the immature brain induce acute and also long-lasting changes in spontaneous activity in humans (Roberts et al, 2014 ) and in rodents, both in vitro and in vivo (Brockmann et al, 2013 ; Ranasinghe et al, 2015 ; Mordel et al, 2016 ).…”

“…Such deleterious insults could be bacterial/viral infection and/or perinatal asphyxia during perinatal stages (Hagberg and Mallard, 2005 ). Experiments mimicking viral (Hartung et al, 2016 ) or bacterial (Nimmervoll et al, 2013 ) infections revealed changes in spontaneous activity patterns and hypoxia-ischemia also alters spontaneous activity in the immature rodent and human brain (Roberts et al, 2014 ; Ranasinghe et al, 2015 ; Mordel et al, 2016 ). Thus disturbances of neuronal activity under these conditions should be considered as an additional possible factor in the etiology of schizophrenia, beside other proposed mechanisms (Lisman et al, 2008 ).…”

Impact of glycolysis inhibitor (2-DG) and oxidation and phosphorylation uncoupler (2,4-DNP) on brain metabolites

“…Исследование изменений нейрометаболитов, вызванных введением 2ДГ, выполненное на крысах линии Sprague Dawley, как и в предыдущих (Moshkin et al, 2014) иссле- (Mordel et al, 2016;Dang et al, 2017).…”