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Temporal lobe epilepsy is characterized by recurrent seizures in one or both temporal lobes of the brain; some  in vitro  models show that epileptiform discharges initiate in entorhinal layer V neurons and then spread into other areas of the temporal lobe. We previously found that, in the presence of GABA A  receptor antagonists, stimulation of afferent fibers, terminating both at proximal and distal dendritic locations, initiated hyperexcitable bursts in layer V medial entorhinal neurons. We investigated the differential contribution of Ca 2+ -dependent mechanisms to the plateaus underlying these bursts at proximal and distal synapses. We found that the NMDA glutamatergic antagonist D,L-2-amino-5-phosphonovaleric acid (APV; 50 μM) reduced both the area and duration of the bursts at both proximal and distal synapses by about half. The L-type Ca 2+  channel blocker nimodipine (10 μM) and the R- and T-type Ca 2+  channel blocker NiCl 2  (200 μM) decreased the area of the bursts to a lesser extent; none of these effects appeared to be location-dependent. Remarkably, the perfusion of flufenamic acid (FFA; 100 μM), to block Ca 2+ -activated non-selective cation currents ( I  CAN ) mediated by transient receptor potential (TRP) channels, had a location-dependent effect, by abolishing burst firing and switching the suprathreshold response to a single action potential (AP) for proximal stimulation, but only minimally affecting the bursts evoked by distal stimulation. A similar outcome was found when FFA was pressure-applied locally around the proximal dendrite of the recorded neurons and in the presence of a selective blocker of melastatin TRP (TRPM) channels, 9-phenanthrol (100 μM), whereas a selective blocker of canonical TRP (TRPC) channels, SKF 96365, did not affect the bursts. These results indicate that different mechanisms might contribute to the initiation of hyperexcitability in layer V neurons at proximal and distal synapses and could shed light on the initiation of epileptiform activity in the entorhinal cortex.

Differential Contribution of Ca2+-Dependent Mechanisms to Hyperexcitability in Layer V Neurons of the Medial Entorhinal Cortex