Abstracts

Hypoxia is the most common cause of neonatal seizures, and newborns who experienced such seizures are at higher risk of later epilepsy. To develop therapies to minimize this epilepsy risk, we first need to identify changes in brain function that result from such seizures. Using a rodent model, we previously observed a pathological decrease in tonic synaptic inhibition of hippocampal CA1 pyramidal neurons several days after neonatal hypoxia-induced seizures. We now aimed to more precisely determine the time course of changes in inhibition to begin to elucidate underlying mechanisms that could contribute to chronic hippocampal hyper-excitability and increased seizure susceptibility.
Seizures were induced in Long-Evans rat pups on postnatal day 10 by exposure to global hypoxia (5-6% O[sub]2[/sub]) for 15 minutes. Hippocampal slices were prepared from hypoxia-treated and age-matched control pups at various times from 10 minutes to 7 days post-hypoxia. Whole-cell voltage-clamp recordings were obtained from CA1 pyramidal neurons. Spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded at the reversal potential for glutamate receptors (+10 mV) to observe tonic inhibitory synaptic events with the slice circuitry largely intact. sIPSC amplitudes and frequency were compared between groups at each time point.
The amplitudes and frequency of sIPSCs were decreased in neurons from the hypoxia-treated group compared to controls at all time points tested. However, the magnitudes of these decreases differed with time after hypoxia. Mean sIPSC [underline]amplitudes[/underline] were decreased to 79% of control immediately following hypoxia treatment, were further decreased to 50% of control by 3-4 days post-hypoxia, and recovered to 90% of control within 7 days. In contrast, sIPSC [underline]frequency[/underline] was decreased to 40-60% of control immediately after hypoxia treatment and remained comparably decreased through 7 days post-hypoxia.
The difference in time courses of altered sIPSC amplitudes versus frequency following hypoxia-induced seizures indicated that these are mediated by multiple mechanisms. Recovery of sIPSC amplitudes suggested that possible decreases in GABA release or postsynaptic efficacy are transient following hypoxia-induced seizures, and thus, may enable epileptogenic plasticity in the short term, but likely do not contribute directly to chronic hippocampal hyper-excitability. In contrast, the persistent decrease in sIPSC frequency may indicate mechanisms that contribute directly to chronically increased hippocampal hyper-excitability and seizure propensity. Possible mechanisms include a chronic decrease in the excitability of presynaptic interneurons, a loss of inhibitory synapses, or altered mechanisms of presynaptic GABA release.
[Supported by: An award to the University of Texas Health Science Center at San Antonio for the Research Resources Program for Medical Schools of the Howard Hughes Medical Institute (RMS), and by American Heart Association Scientist Development Grant 0330184N (RMS). ]