Calcium signaling in astroglial cells. Noradrenergic effects and regulation

Abstract: Astroglial cells are the most common cell type in the central nervous system and express a wide array of ion channels and neurotransmitter receptors. The cells organize into multicellular networks and exhibit a calcium-based excitability in which receptor-mediated calcium elevations propagate as intercellular waves over considerable distances. Astrocytes greatly contribute to the maintenance of extracellular homeostasis and have the ability to release neurotransmitter substances in response to neuronal activity. This bi-directional communication between neurons and astrocytes may lead to profound changes in neuronal excitability and synaptic transmission. The astrocytes also constitute major targets for noradrenergic signaling, which mediates events such as increased glucose metabolism, glutamate uptake and metabolism and the secretion of neurotrophins. The overall aim of this thesis was to evaluate the effects of noradrenergic stimulation on astrocytes concerning intracellular calcium and potassium dynamics, calcium-based cell-to-cell communication and glutamate-mediated glutamate release. The results demonstrate distinct differences between neurons and astrocytes in regard to changes in intracellular calcium and potassium concentrations. They further show that b-adrenoceptor activation opens calcium-dependent potassium channels in astrocytes, which implies a dynamic role for noradrenaline in the control of the astroglial buffering of extracellular potassium. Further, a1-adrenergic activation was shown to modify astroglial calcium waves, which in turn indicates a noradrenergic regulation of cellular coordination within the astroglial syncytium. The results also show that the nature of calcium responses is diverse after a1-adrenoceptor and metabotropic glutamate receptor activation, suggesting that astrocytes are capable of discriminating between excitatory inputs. Furthermore, the synchronization of calcium release sites is suggested to determine the properties of oscillatory changes in intracellular calcium. The present study also demonstrates that glutamate-induced oscillatory calcium changes are regulated and modulated by the interplay between the glutamatergic and noradrenergic systems. Further, the results provide evidence for receptor specificity in astroglial glutamate-induced glutamate release and describe how a1-adrenergic activation impairs the release. In summary, the results indicate that activation of noradrenergic astroglial receptors can modify astroglial-neuronal interactions. The findings also provide additional evidence that supports the upcoming hypothesis by which astroglial cells are considered active participants in signal processing in the brain.