Surviving granule cells of the sclerotic human hippocampus have reduced Ca2+ influx because of a loss of calbindin-D(28k) in temporal lobe epilepsy

Abstract

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 Ca2+-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 Ca2+ influx into human neurons. In patients with Ammon's horn sclerosis (AHS), the loss of CB from GCs markedly increased the Ca2+-dependent inactivation of voltage-dependent Ca2+ currents (I(Ca)), thereby diminishing Ca2+ influx during repetitive neuronal firing. Introducing purified CB into GCs restored Ca2+ 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 Ca2+ influx through an enhanced Ca2+-dependent inactivation of voltage-dependent Ca2+ channels during prolonged neuronal discharges, the loss of CB may contribute to the resistance of surviving human granule cells in AHS.