Suppression of Spreading Depression-Like Events in Locusts by Inhibition of the NO/cGMP/PKG Pathway

Abstract

Despite considerable research attention focused on mechanisms underlying neural spreading depression (SD), because of its association with important human CNS pathologies, such as stroke and migraine, little attention has been given to explaining its occurrence and regulation in invertebrates. In the locust metathoracic ganglion (MTG), an SD-like event occurs during heat and anoxia stress, which results in cessation of neuronal output for the duration of the applied stress. SD-like events were characterized by an abrupt rise in extracellular potassium ion concentration ([K ϩ ] o ) from a baseline concentration of ϳ8 to Ͼ30 mM, which returned to near baseline concentrations after removal of the applied stress. After return to baseline [K ϩ ] o , neuronal output (ventilatory motor pattern activity) from the MTG recovered. Unlike mammalian neurons, which depolarize almost completely during SD, locust neurons only partially depolarized. SD-like events in the locust CNS were suppressed by pharmacological inhibition of the nitric oxide/cyclic guanosine monophosphate/protein kinase G (NO/cGMP/PKG) pathway and were exacerbated by its activation. Also, environmental stressors such as heat and anoxia increased production of nitric oxide in the locust CNS. Finally, for the intact animal, manipulation of the pathway affected the speed of recovery from suffocation by immersion under water. We propose that SD-like events in locusts provide an adaptive mechanism for surviving extreme environmental conditions. The highly conserved nature of the NO/cGMP/PKG signaling pathway suggests that it may be involved in modulating SD in other organisms, including mammals.

Critical role for protein kinase A in the acquisition of gregarious behavior in the desert locust

“…KT5823, an inhibitor of PKG previously used in S. gregaria (36,52), did not significantly affect behavioral phase state after acute crowding, nor did it cause long-term gregarious locusts to behave less gregariously. Injection of dsRNA against for was likewise ineffective despite causing a 60% reduction in FOR protein expression in the CNS.…”

Metabolic Stress Modulates Motor Patterning via AMP-Activated Protein Kinase

“…Time to succumb was measured as the length of time between immersion under water and the observed seizure-like convulsions of the whole animal. After removal from the water, locusts were placed on their side on a piece of paper towel, and the time to recover ventilation was measured (Armstrong et al, 2009). The effects of starvation and of AICAR and compound-C on vulnerability to submersion under water were most clearly seen in locusts starved for 4 d and thus these results are presented; however, the results for 2 and 6 d of starvation were qualitatively similar.…”

“…, an AMPK inhibitor, into the hemocoel (Armstrong et al, 2009). Control locusts were injected with standard locust saline containing 0.5% DMSO.…”

“…Locusts are tolerant of oxygen deprivation and can withstand hours of submersion under water (Armstrong et al, 2009) by entering a reversible stress-induced coma. Upon removal from anoxic conditions, nervous and muscular systems completely recover and locusts behave normally.…”

“…Upon removal from anoxic conditions, nervous and muscular systems completely recover and locusts behave normally. Stress-induced coma, including arrest of vCPG operation, is associated with spreading depression (SD)-like events that share properties of SD in mammalian cerebral cortical tissue (Rodgers et al, 2007Armstrong et al, 2009). These are characterized by abrupt 50 -80 mM increases in extracellular potassium concentration ([K ϩ ] o ) within the ventilatory neuropile that coincide with vCPG shutdown.…”