Metabolic Stress Modulates Motor Patterning via AMP-Activated Protein Kinase

Abstract

Neural circuits are especially vulnerable to metabolic stress. The locust (Locusta migratoria) responds to anoxia by entering a coma during which neural and muscular systems shut down. During anoxic coma, arrest of the ventilatory central pattern generator is tightly correlated with an abrupt spreading depression (SD)-like increase in extracellular potassium concentration within the metathoracic neuropile. We examined the role of the AMP-activated protein kinase (AMPK), an evolutionarily conserved sensor of cellular energy status, in anoxia-induced ventilatory arrest and SD-like events in the locust. Perfusion of sodium azide (NaN(3); mitochondrial toxin) induced SD, temporary coma, and profound changes in the ventilatory motor pattern characterized as a rapid rhythm before coma and a slower rhythm following recovery. AMPK activation using 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) mimicked the motor pattern changes induced by NaN(3) but did not induce SD and coma. The effects of NaN(3) on the ventilatory rhythm were reversed by perfusion of compound-C (AMPK inhibitor) or glucose, and the effects of AICAR were also reversed by compound-C, confirming the modulatory roles of AMPK and energy status. Ouabain-induced recurring SD was suppressed by inhibition of AMPK and exacerbated by its activation. We show that the motor pattern changes induced by metabolic stress are not the result of SD alone, but that AMPK is necessary and sufficient for these changes and that AMPK activity strongly influences susceptibility to SD.