Paradoxical Ca 2+ Rises induced by Low External Ca 2+ in Rat Hippocampal Neurones

Confocal Ca 2+ imaging of rat hippocampal slices shows a paradoxical effect of acute reductions of the [Ca 2+ ] o . Upon slice perfusion with low‐Ca 2+ media, a prompt intracellular Ca 2+ rise selectively occurs in neurones. This response is observed only in slices challenged with agonists of group I metabotropic glutamate or M 1 muscarinic receptors. In contrast, the intracellular Ca 2+ level of non‐stimulated neurones is insensitive to reductions of [Ca 2+ ] o . The phenomenon is observed in 20–25 % of cultured cortical neurones. Evidence is provided demonstrating that: (1) this paradoxical response is not due to a non‐specific decrease in divalent cation concentration but it is selectively activated by a reduction in [Ca 2+ ] o , being maximal with [Ca 2+ ] o between 0.25 and 0.5 m m ; (2) upon maximal stimulation, 70–90 % of CA1‐CA3 pyramidal neurones sense a reduction in [Ca 2+ ] o ; a weaker response is observed in neurones from the neocortex, whereas neurones from the dentate gyrus and granule cells from the cerebellum fail to respond; (3) conditions that elicit paradoxical Ca 2+ responses cause depolarisation and increase the firing rate of hippocampal neurones; (4) paradoxical Ca 2+ rises depend, primarily, on Ca 2+ influx through L‐type voltage‐operated Ca 2+ channels and to a lesser extent on release from intracellular Ca 2+ stores. Inhibition of phospholipase C or protein kinase C failed to suppress the neuronal response, whereas a selective inhibitor of the Src‐family of tyrosine kinases abolishes the paradoxical neuronal Ca 2+ rise. A model is presented to explain how this response is elicited by contemporaneous reduction of the [Ca 2+ ] o and metabotropic receptor stimulation; implications for the pathophysiology of the CNS are also discussed.