Metabolic coupling between glia and neurons is necessary for maintaining respiratory activity in transverse medullary slices of neonatal mouse

The respiratory rhythm is generated and regulated by a neuronal network wit hin the lower brainstem. While the neuronal mechanisms of rhythm generation have been extensively investigated, the contribution of glial cells remain s to be determined. Here we report the effect of specific blockade of the g lial Krebs cycle and glutamine synthetase on the neuronal activity of the r espiratory network. Application of 5 mm fluoroacetate, which selectively bl ocks the glial Krebs cycle, suppressed rhythmic respiratory burst activity. Substitution of either the Krebs cycle substrate isocitrate (3 mm) or glut amine (3 mm) restored rhythmic network activity. Blockade of glutamine synt hetase by methionine sulfoximine (0.5 mm) suppressed rhythmic burst activit y as well. Resubstitution of glutamine (3 mm) was able to restore rhythmic activity in the presence of methionine sulfoximine. This data demonstrates that the glutamate-glutamine cycle in astrocytes and their supply of glutam ine to neuronal glutamatergic terminals is essential for the rhythm generat ion in the respiratory centre.