Inositol-1,4,5-trisphosphate receptor-mediated Ca2+ waves in pyramidal neuron dendrites propagate through hot spots and cold spots

We studied inositol-1,4,5-trisphosphate (IP3) receptor-dependent intracellular Ca2+ waves in CA1 hippocampal and layer V medial prefrontal cortical pyramidal neurons using whole-cell patch-clamp recordings and Ca2+ fluorescence imaging. We observed that Ca2+ waves propagate in a saltatory manner through dendritic regions where increases in the intracellular concentration of Ca2+ ([Ca2+](i)) were large and fast ('hot spots') separated by regions where increases in [Ca2+](i) were comparatively small and slow ('cold spots'). We also observed that Ca2+ waves typically initiate in hot spots and terminate in cold spots, and that most hot spots, but few cold spots, are located at dendritic branch points. Using immunohistochemistry, we found that IP3 receptors (IP(3)Rs) are distributed in clusters along pyramidal neuron dendrites and that the distribution of inter-cluster distances is nearly identical to the distribution of inter-hot spot distances. These findings support the hypothesis that the dendritic locations of Ca2+ wave hot spots in general, and branch points in particular, are specially equipped for regenerative IP3R-dependent internal Ca2+ release. Functionally, the observation that IP3R-dependent [Ca2+](i) rises are greater at branch points raises the possibility that this novel Ca2+ signal may be important for the regulation of Ca2+-dependent processes in these locations. Futhermore, the observation that Ca2+ waves tend to fail between hot spots raises the possibility that influences on Ca2+ wave propagation may determine the degree of functional association between distinct Ca2+-sensitive dendritic domains.