Store-operated calcium entry modulates neuronal network activity in a model of chronic epilepsy

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Abstract

Store-operated Ca2+ entry (SOCE) over the plasma membrane is activated by depletion of intracellular Ca2+ stores and has only recently been shown to play a role in CNS processes like synaptic plasticity. However, the direct effect of SOCE on the excitability of neuronal networks in vitro and in vivo has never been determined. We confirmed the presence of SOCE and the expression of the calcium sensors STIM1 and STIM2, which convey information about the calcium load of the stores to channel proteins at the plasma membrane, in neurons and astrocytes. Inhibition of SOCE by pharmacological agents 2-APB and ML-9 reduced the steady-state neuronal Ca2+ concentration, reduced network activity, and increased synchrony of primary neuronal cultures grown on multi-electrode arrays, which prompted us to elucidate the relative expression of STIM proteins in conditions of pathologic excitability. Both proteins were increased in brains of chronic epileptic rodents and strongly expressed in hippocampal specimens from medial temporal lobe epilepsy patients. Pharmacologic inhibition of SOCE in chronic epileptic hippocampal slices suppressed interictal spikes and rhythmized epileptic burst activity. Our results indicate that SOCE modulates the activity of neuronal networks in vitro and in vivo and delineates SOCE as a potential drug target.

Highlights

□ Calcium sensors STIM1 and STIM2 are present in neurons and astrocytes. □ Inhibition of SOCE reduces steady-state calcium in neurons but not in astrocytes. □ Inhibition of SOCE dampens and synchronizes network activity in multi-electrode arrays. □ STIM1 and STIM2 are increased in brains of chronic epileptic rodents. □ Inhibition of SOCE in chronic epileptic hippocampal slices rhythmizes epileptic bursts.

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