Calcium stores regulate excitability in cultured rat hippocampal neurons.

Extracellular calcium ions support synaptic activity, but also reduce excitability of central neurons. In the present study, the effect of calcium on excitability was explored in cultured hippocampal neurons. CaCl2 injected by pressure in the vicinity of a neuron that is bathed only in MgCl2 as the main divalent cation, caused a depolarizing shift in action potential threshold and a reduction in excitability. This effect was not seen if the intracellular milieu consisted of Cs+ instead of K-gluconate as the main cation, or when it contained ruthenium red, which blocks release of calcium from stores. The suppression of excitability by calcium was mimicked by caffeine, and calcium store antagonists CPA or thapsigargin blocked this action. Neurons taken from synaptopodin (SP)- knockout mice show significantly reduced efficacy of calcium modulation of action potential threshold. Likewise, in Orai-1 knockdown cells calcium is less effective in modulating excitability of neurons. Activation of SK channels increased action potential threshold akin to that produced by calcium ions, whereas blockade of SK channels but not BK channels reduced the threshold for action potential discharge. These results indicate that calcium released from stores may suppress excitability of central neurons.