, 2005). Thus, it was somewhat surprising that neuropeptide-deficient mutants, which are Entinostat manufacturer all strongly aldicarb resistant, have unaltered baseline synaptic physiology. Our results provide an explanation for this puzzle. We show that brief aldicarb treatments induce a form of synaptic potentiation, which is abolished in the neuropeptide-deficient mutants. Several aspects of these results are significant. These results represent the first C. elegans paradigm for activity-induced synaptic potentiation, and the first

study to document an electrophysiological effect of an endogenous C. elegans neuropeptide. Our results also suggest that additional genes involved in synaptic plasticity will be found among the

genes identified in the prior screens for aldicarb-resistant mutants. Here we show that secretion of NLP-12 potentiates synaptic transmission at cholinergic NMJs, and that it does so by enhancing ACh release. Aldicarb treatment enhanced cholinergic transmission, which was manifested by an increase both in the rate of EPSCs and in the total synaptic charge evoked by a depolarizing stimulus. Both effects of aldicarb were eliminated by mutations inactivating NLP-12 and CKR-2 (an NLP-12 receptor). NLP-12 is expressed by a single neuron DVA, and aldicarb treatment induces NLP-12 secretion from these neurons. Collectively, these results support the idea that aldicarb treatment evokes NLP-12 secretion from DVA neurons, which subsequently potentiates cholinergic and transmission. Several results Akt inhibitor suggest that the NLP-12-mediated potentiation occurs by a presynaptic mechanism. First, the increase in endogenous EPSCs frequency is characteristic of a presynaptic change. Second, the amplitude and kinetics of endogenous EPSCs were not altered by aldicarb treatment,

implying that muscle responses to individual synaptic quanta were unaltered. Third, ACh-activated muscle currents were not increased by aldicarb, suggesting that increased muscle sensitivity to ACh is unlikely to explain the aldicarb-induced synaptic potentiation. In fact, aldicarb treatment significantly decreased ACh-activated current amplitudes, consistent with decreased muscle sensitivity to ACh. Identical decreases in ACh-activated currents were observed in aldicarb treated nlp-12 and ckr-2 mutants, suggesting that this effect was not mediated by NLP-12. Fourth, the ckr-2 mutant defects in aldicarb-induced potentiation, aldicarb-induced paralysis, and locomotion rate were all rescued by transgenes expressing CKR-2 in the presynaptic cholinergic neurons. Fifth, a ckr-2 transcriptional reporter was expressed in cholinergic motor neurons, but was not expressed in body muscles. Collectively, these results all support the idea that increased ACh release accounts for NLP-12-mediated potentiation of synaptic transmission.