Calcium-induced calcium release and type 3 ryanodine receptors modulate the slow afterhyperpolarising current, sI(AHP), and its potentiation in hippocampal pyramidal neurons

The slow afterhyperpolarising current, sI(AHP), is a Ca2+-dependent current that plays an important role in the late phase of spike frequency adaptation. sI(AHP)is activated by voltage-gated Ca(2+)channels, while the contribution of calcium from ryanodine-sensitive intracellular stores, released by calcium-induced calcium release (CICR), is controversial in hippocampal pyramidal neurons. Three types of ryanodine receptors (RyR1-3) are expressed in the hippocampus, with RyR3 showing a predominant expression in CA1 neurons. We investigated the specific role of CICR, and particularly of its RyR3-mediated component, in the regulation of the sI(AHP)amplitude and time course, and the activity-dependent potentiation of the sI(AHP)in rat and mouse CA1 pyramidal neurons. Here we report that enhancement of CICR by caffeine led to an increase in sI(AHP)amplitude, while inhibition of CICR by ryanodine caused a small, but significant reduction of sI(AHP). Inhibition of ryanodine-sensitive Ca(2+)stores by ryanodine or depletion by the SERCA pump inhibitor cyclopiazonic acid caused a substantial attenuation in the sI(AHP)activity-dependent potentiation in both rat and mouse CA1 pyramidal neurons. Neurons from mice lacking RyR3 receptors exhibited a sI(AHP)with features undistinguishable from wild-type neurons, which was similarly reduced by ryanodine. However, the lack of RyR3 receptors led to a faster and reduced activity-dependent potentiation of sI(AHP). We conclude that ryanodine receptor-mediated CICR contributes both to the amplitude of the sI(AHP)at steady state and its activity-dependent potentiation in rat and mouse hippocampal pyramidal neurons. In particular, we show that RyR3 receptors play an essential and specific role in shaping the activity-dependent potentiation of the sI(AHP). The modulation of activity-dependent potentiation of sI(AHP)by RyR3-mediated CICR contributes to plasticity of intrinsic neuronal excitability and is likely to play a critical role in higher cognitive functions, such as learning and memory.

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