Modulation of AChR and GABA_R can restore post-synaptic folding.

Abstract

<p>(A) At the <i>C. elegans</i> NMJ, the functional balance between GABA_R and AChR signaling regulates post-synaptic muscle function. (B) L-AChR activation with the agonist levamisole (in water) suppressed Q35 aggregation at 5 µM, but enhanced aggregation at 50 µM. Mutant AChR <i>unc-38(e264)</i> is a control for AChR-mediated effect. (C) Reduction in GABA_R function with lindane (in 10% EtOH) suppressed Q35 aggregation at 25 µM, and enhanced aggregation at 1 mM concentration (relative to EtOH control treatment). (D) Effect on Q35 aggregation by decrease in GABA with <i>unc-49</i> or <i>unc-47</i> RNAi, and by inhibition of GABA in <i>unc-47(gk192)</i> or <i>unc-30(e191)</i> mutant backgrounds. (E) Incubation with 50–200 mM GABA (in water) suppressed Q35 aggregation. GABA at 50 mM abolished the suppressor effect of <i>gei-11</i>, by “re-balancing” the GABAergic-cholinergic signaling. (F) Real-time qPCR analysis of <i>hsp-70</i> (<i>C12C8.1, F44E5.4</i>) levels in 5 day old wt animals upon treatment with ACh, levamisole or the GABA_R antagonist Lindane, or upon decrease in GABAergic signaling by either RNAi or mutant backgrounds of <i>unc-47(gk192)</i>, <i>unc-49(e407)</i> or <i>unc-30(e191)</i>. Student t-test **<i>p</i><0.01 and ***<i>p</i><0.001; data and statistics are relative to Q35;vector control (±SD) (RNAi controls: <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003711#pgen.1003711.s008" target="_blank">Table S1</a>).</p