Methylxanthine‐evoked seizure‐like perturbation of isolated newborn rat hippocampal and cortical networks

Abstract

Treatment of (preterm) infants with caffeine and theophylline for stabilization of breathing can evoke seizures. Here, we studied in brain slices from 1–10 days‐old rats whether these methylxanthines affect early network oscillations (ENOs) in hippocampal and cortical areas that occur at rates of 15–45/min and 0.5–3/min, respectively, and presumably promote connectivity. Bath‐applied caffeine or theophylline did not substantially perturb either type of ENOs at <0.5 mM whereas 0.5–10 mM transformed ENOs into slow (0.5–5/min) large amplitude seizure‐like discharges resembling those upon GABAA receptor blockade using gabazine (1–5 μM). Both methylxanthines also provoked spontaneous and electrically‐evoked epileptiform activity in an in‐toto hippocampus preparation from 1–10 days old rats, with theophylline being more effective at low millimolar concentrations similar to its more potent action on ENOs. Findings suggest that >0.5 mM theophylline (and higher doses of caffeine) perturbs both spontaneous bursting and evoked synaptic processes in hippocampal and cortical neural networks. If such methylxanthine levels were reached in these brain structures during clinical administration, which can last for several weeks, development of connectivity may be hampered.