Entorhinal cortex lesions result in adenosine-sensitive high frequency oscillations in the hippocampus

Entorhinal cortex (EC) projections to the hippocampus run along the perforant path and activate the hippocampal area CA3 and the dentate gyrus (DG), which, in turn, drives CA3. Because cortical trauma damages the source of inputs to the hippocampus, we hypothesize that such an event can be reflected in immediate alterations of the hippocampal oscillatory activity. We here explore whether acute, localized disruption of EC-EC connectivity is involved in the generation or modulation of high frequency oscillations (HFOs) in the hippocampus. We conducted in vitro electrophysiological recordings in CA3 and DG of combined EC-hippocampal transversal slices prepared from intact brains and from brains with a spatially defined, transversal cut of the EC made in situ, 2h before in vitro recordings commenced. We also determined if pharmacological manipulations of the adenosine system modulated the fast oscillatory activity. EC-hippocampal slices prepared from brains, in which a transversal lesion of the EC was uni- or bilaterally conducted in situ, displayed spontaneous epileptiform events with superimposed ripples (150-250 Hz) and fast ripples (>250 Hz), whereas those obtained from non-lesioned brains did not have spontaneous HFOs. However, in the latter, high frequency stimulation applied to the perforant path produced ripple activity in area CA3. Spontaneous fast ripples were prevented by conducting the slicing procedure and incubating the slices both in a Na(+)-free medium and in a low Ca(++)-high Mg(++) medium for an hour before recording commenced, under normal Na(+) concentration. Activation of A1, but not A2, receptors produced a strong inhibition of the incidence and spectral power of fast ripples but did not change their intrinsic frequency. Our data show that the disruption of EC-to-EC connections can immediately disinhibit hippocampal CA3 area to generate HFOs on top of epileptiform events, probably constituting an irritating focus long before overt epileptic activity can be detected behaviorally. Therefore, the activation of the adenosinergic system can possibly be regarded as an immediate intervention strategy to avoid epileptogenesis.