Abstracts

Rationale: Hippocampal sharp wave-ripple complexes (SPW-R) are proposed to participate in memory consolidation during periods of quiet and slow wave sleep. Previous reports have identified the CA3 region as the generation site of SPW-Rs with mossy fiber activity modulating their rate of incidence. Higher therapeutic concentrations of the antiepileptic drug carbamazepine are associated with cognitive side effects. Here, we determined carbamazepine effects on SPW-Rs, synaptic transmission and short-term plasticity (STP) at multiple hippocampal synapses. Methods: Horizontal mouse hippocampal slices were placed on a high density multi-electrode array. Electrodes located in the Schaffer collaterals (SC) or mossy fibers (MF) were used to deliver paired pulse stimulations and evoke field potentials in the CA1 and CA3 regions. Spontaneous SPW-Rs were recorded in all regions before, during and after carbamazepine application. Results: Results: The rank order of carbamazepine efficacy in inhibiting field potentials was SC-CA1>SC-CA3>MF-CA3. The potency order was SC-CA3>MF-CA3>SC-CA1. Carbamazepine was more efficacious inhibiting the second pulse field potential resulting in a ~25-30% decrease of the paired pulse ratio at all three synapses. All parameters of SPW-Rs were nearly abolished by 300 ?M carbamazepine with a potency similar to SC-CA3 inhibition. Regional representation of ripples was restricted to the CA3 region with increasing carbamazepine concentrations. Conclusions: Carbamazepine inhibits SPW-Rs, field potentials, and STP at therapeutic concentrations associated with cognitive side effects. Synapse-specific sensitivity suggests that carbamazepine primarily inhibits the generation of SPW-Rs at CA3 recurrent collaterals. Carbamazepine inhibition at the MF-CA3 and SC-CA3 synapses most likely contributes by reducing the rate of incidence of SPW-Rs and preventing their propagation to the CA1 region.