Frequency Modulation of Synchronized Ca2+ Spikes in Cultured Hippocampal Networks through G-Protein-Coupled Receptors

Synchronized spontaneous Ca2+ spikes in networked neurons represent periodic burst firing of action potentials, which are believed to play a major role in the development and plasticity of neuronal circuitry. How these network activities are shaped and modulated by extrinsic factors during development, however, remains to be studied. Here we report that synchronized Ca2+ spikes among cultured hippocampal neurons can be modulated by two small factors that act on G-protein-coupled receptors (GPCRs): the neuropeptide PACAP (pituitary adenylate cyclase-activating polypeptide) and the chemokine SDF-1 (stromal cell-derived factor-1). PACAP effectively increases the frequency of the synchronized Ca2+ spikes when applied acutely; the PACAP potentiation of Ca2+ spikes requires the activation of the PACAP-specific PAC1 GPCRs and is mediated by the activation of cAMP signaling pathway. SDF-1, on the other hand, significantly reduces the frequency of these Ca2+ spikes through the activation of its specific GPCR CXCR4; the inhibitory action of SDF-1 is mediated by the inhibition of cAMP pathway through the Gi component of GPCRs. Taken together, these results demonstrate that synchronized neuronal network activity can be effectively modulated by physiologically and developmentally relevant small factors that act on GPCRs to target the cAMP pathway. Such modulation of neuronal activity through GPCRs may represent a significant mechanism that underlies the neuronal plasticity during neural development and functioning.