In mesial temporal lobe epilepsy (mTLE), the predominant form of epilepsy in adults, and in animal models of the disease, there is a conspicuous loss of the intracellular Ca(2+)-binding protein calbindin-D(28k) (CB) from granule cells (GCs) of the dentate gyrus. The role of this protein in nerve cell function is controversial, but here we provide evidence for its role in controlling Ca(2+) influx into human neurons. In patients with Ammon's horn sclerosis (AHS), the loss of CB from GCs markedly increased the Ca(2+)-dependent inactivation of voltage-dependent Ca(2+) currents (I(Ca)), thereby diminishing Ca(2+) influx during repetitive neuronal firing. Introducing purified CB into GCs restored Ca(2+) current inactivation to levels observed in cells with normal CB content harvested from mTLE patients without AHS. Our data are consistent with the possibility of neuroprotection secondary to the CB loss. By limiting Ca(2+) influx through an enhanced Ca(2+)-dependent inactivation of voltage-dependent Ca(2+) channels during prolonged neuronal discharges, the loss of CB may contribute to the resistance of surviving human granule cells in AHS.

The persistence of synaptic potentiation in the hippocampus is known to depend on transcription and protein synthesis. We report here that, under regimes of reduced protein synthesis, competition between synapses for the relevant intracellular proteins can be demonstrated. Under such circumstances, the induction of additional protein synthesis-dependent long-term potentiation for a given set of postsynaptic neurons occurs at the expense of the maintenance of prior potentiation on an independent pathway. This new phenomenon, which we call "competitive maintenance," has important functional consequences, and it may be explained in terms of dynamic interactions between synapses and "plasticity factors" over extended periods of time.

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