Regulation of neurite growth by spontaneous Ca2+ oscillations in astrocytes

Astrocytes play a pivotal role in the regulation of neurite growth, but the intracellular signaling mechanism in astrocytes that mediates this regulation remains unclarified. We studied the relationship between spontaneous Ca(2+) oscillations in astrocytes and the astrocyte-mediated neurite growth. We generated Ca(2+) signal-deficient astrocytes in which spontaneous Ca(2+) oscillations were abolished by a chronic inhibition of IP(3) signaling. When hippocampal neurons were cultured on a monolayer of Ca(2+) signal-deficient astrocytes, the growth of dendrites and axons was inhibited. Time-lapse imaging of the advancement of axonal growth cones indicated the involvement of membrane-bound molecules for this inhibition. Among six candidate membrane-bound molecules that may modulate neuronal growth, N-cadherin was downregulated in Ca(2+) signal-deficient astrocytes. Although a blocking antibody to N-cadherin suppressed the axonal growth on control astrocytes, extrinsic N-cadherin expression rescued the suppressed axonal growth on Ca(2+) signal-deficient astrocytes. These findings suggest that spontaneous Ca(2+) oscillations regulate the astrocytic function to promote neurite growth by maintaining the expression of specific growth-enhancing proteins on their surface, and that N-cadherin is one of such molecules.