Synchronization of GABAergic Inputs to CA3 Pyramidal Cells Precedes

25 Here we address how dynamics of glutamatergic and GABAergic synaptic input to CA3 26 pyramidal cells contribute to spontaneous emergence and evolution of recurrent seizure-like 27 events (SLEs) in juvenile (P10-13) rat hippocampal slices bathed in low-[Mg] artificial 28 cerebrospinal fluid. In field potential recordings from CA3 pyramidal layer a short epoch of 29 high frequency oscillation (HFO; 400-800 Hz) was observed during the first 10 ms of SLE 30 onset. GABAergic synaptic input currents to CA3 pyramidal cells were synchronized and 31 coincided with HFO, while the glutamatergic input lagged by ~10 ms. If the intracellular [Cl] 32 remained unperturbed (cell-attached recordings) or was set high with whole-cell electrode 33 solution, CA3 pyramidal cell firing peaked with HFO and GABAergic input. By contrast, 34 with low intracellular [Cl], spikes of CA3 pyramidal cells lagged behind HFO and 35 GABAergic input. This temporal arrangement of HFO, synaptic input sequence, synchrony of 36 GABAergic currents, and pyramidal cell firing emerged gradually with preictal discharges 37 until the SLE onset. Blockade of GABAA receptor mediated currents by picrotoxin reduced 38 the inter-SLE interval and the number of preictal discharges, and did not block recurrent 39 SLEs. Our data suggest that dynamic changes of the functional properties of GABAergic 40 input contribute to ictogenesis and GABAergic and glutamatergic inputs are both excitatory 41 at the instant of SLE onset. At the SLE onset GABAergic input contributes to synchronisation 42 and recruitment of pyramidal cells. We conjecture that this network state is reached by an 43 activity-dependent shift in GABA reversal potential during the preictal phase. 44