A physiologically-validated rat model of term birth asphyxia with seizure generation after, not during, brain hypoxia

Birth asphyxia (BA) is often associated with seizures which emerge during the recovery and may exacerbate the ensuing hypoxic-ischemic encephalopathy. In rodent models of BA, exposure to hypoxia is used to evoke seizures, which commence already during the insult. Here, we introduce a term-equivalent model of BA, in which seizures are triggered after, not during, brain hypoxia. Postnatal day 11-12 rat pups were exposed either to steady asphyxia (15 min; 5 % O2 + 20 % CO2) or to intermittent asphyxia (30 min; three 5+5 min cycles of 9 % and 5 % O2 at constant 20 % CO2). Cortical activity and seizures were recorded in freely-behaving animals. Simultaneous electrode measurements of cortical local field potentials (LFP) and intracortical pH and Po2 were made under urethane-anesthesia. Both protocols decreased blood pH to <7.0 and base excess by 20 mmol/l, and evoked an increase in plasma copeptin (0.2 to 5 nM). Clonic and tonic convulsions were triggered after intermittent but not steady asphyxia, and they were tightly associated with electrographic seizures. During intermittent asphyxia LFP activity was suppressed as brain pH decreased from 7.3 to 6.7. Brain Po2 fell below detection level in 5 % ambient O2 but returned to the baseline level during steps to 9 % O2. Neuronal hyperexcitability and seizures were suppressed in all types of experiments when the post-asphyxia brain pH recovery was slowed down by 5 % CO2. Our data suggest that the recurring hypoxic episodes during intermittent asphyxia promote neuronal excitability, which becomes established as hyperexcitability and seizures only after the suppressing effect of the hypercapnic acidosis is relieved. The present rodent model of BA is to our knowledge the first one in which, consistent with clinical BA, robust behavioral and electrographic seizures are triggered after and not during the BA-mimicking insult.