Abstracts

Rationale: Early life seizures are often refractory to conventional antiepileptic drugs, and can result in later life epilepsy, cognitive deficits including autism. Using an established neonatal hypoxic seizure (HS) model, we have previously shown an impairment of LTP in hippocampal slices removed from rats at 48-72h following HS, which is in part due to seizure-induced reduction of silent synapses. However, our results also show an unexpected occlusion of NMDA-dependent LTD. The threshold for both LTP and LTD can be modulated by priming neuronal network activities, displaying "metaplasticity". Given changes in both LTP and LTD following HS, we hypothesize that HS can evoke a rightward shift of metaplastic modulation of LTP and LTD. Methods: HS were induced by acute global hypoxia in P10 rats. Ex vivo hippocampal slices were prepared from rats at 48-72h following HS as well as their littermate controls. Whole-cell current clamp recordings were made in hippocampal CA1 pyramidal neurons from post-HS 48h pups and littermate controls. Extracellular field potential (fEPSP) recordings were obtained from the apical dendritic layer (stratum radiatum) of the CA1 region by stimulating the Schaffer collateral pathway. fEPSP slopes were measured before and after a train of stimulation at 0.1, 1Hz (1200pulses), 5, 10, 20 Hz (900pulses) and two trains of 100Hz (100pulses, 20s interval). Results: We found that CA1 neurons from post-HS slices showed a significant increase in spontaneous firing of action potentials compared to neurons from control slices (n=5-6, p<0.05). Consistent with previous findings, the potentiation of fEPSP slopes in response to 100Hz stimulation was significantly attenuated in post-HS slices (potentiated by 10.6 ± 7.2%, n=6, p<0.05) compared to those from P12-13 controls (potentiated by 58.3 ± 18.7%, n=5). The depression of fEPSP slopes in response to 1Hz stimulation was also significantly attenuated in post-HS slices (reduced by 19.4 ± 7.6%, n=7, p<0.05) compared to those from P12-13 controls (reduced by 59.2 ± 11.9%, n=5). In addition, HS induced a rightward shift of the LTP/LTD induction threshold (5Hz: -25.8±5.6%, n=5; 10Hz: -11.2±6.6%, n=6; 20Hz: -12.7±7.6%, n=7) compared to littermate controls (5Hz: -20.5±7.2%, n=4; 10Hz: 3.6±9.2%, n=4; 20Hz: 20.6±5.8%, n=5). Conclusions: Our data show a metaplastic modulation of LTP/LTD induction in the hippocampus following HS, suggesting that the early life seizure-induced LTP/LTD impairment might be modifiable and treatable by both pharmacologic agents and activity or stimulation such as TMS.