SUMMARY Neural circuits have long been known to modulate myogenic muscles such as the heart, yet a mechanistic understanding at the cellular and molecular levels remains limited. We studied how light inhibits pumping of the Caenorhabditis elegans pharynx, a myogenic muscular pump for feeding, and found three neural circuits that alter pumping. First, light inhibits pumping via the I2 neuron monosynaptic circuit. Our electron microscopic reconstruction of the anterior pharynx revealed evidence for synapses from I2 onto muscle that were missing from the published connectome, and we show that these "missed synapses" are likely functional. Second, light inhibits pumping through the RIP-I1-MC neuron polysynaptic circuit, in which an inhibitory signal is likely transmitted from outside the pharynx into the pharynx in a manner analogous to how the mammalian autonomic nervous system controls the heart. Third, light causes a novel pharyngeal behavior, reversal of flow or "spitting," which is induced by the M1 neuron. These three neural circuits show that neurons can control a myogenic muscle organ not only by changing the contraction rate but also by altering the functional consequences of the contraction itself, transforming swallowing into spitting. Our observations also illustrate why connectome builders and users should be cognizant that functional synaptic connections might exist despite the absence of a declared synapse in the connectome.

We are interested in the allosteric modulation of neuronal nicotinic acetylcholine receptors (nAChRs). We have postulated that the anthelmintic morantel (Mor) positively modulates (potentiates) rat ␣3␤2 receptors through a site located at the ␤(ϩ)/␣(Ϫ) interface that is homologous to the canonical agonist site (J Neurosci 29: 8734 -8742, 2009). On this basis, we aimed to determine the site specificity by studying differences in modulation between ␣3␤2 and ␣4␤2 receptors. We also compared modulation by Mor with that of the related compound oxantel (Oxa). Whereas Mor and Oxa each potentiated ␣3␤2 receptors 2-fold at saturating acetylcholine (ACh) concentrations, Mor had no effect on ␣4␤2 receptors, and Oxa inhibited AChevoked responses. The inhibition was noncompetitive, but not due to open channel block. Furthermore, the nature and extent of modulation did not depend on subunit stoichiometry. We studied six positions at the ␣(Ϫ) interface that differ between ␣3 and ␣4. Two positions (␣3Ile57 and ␣3Thr115) help mediate the effects of the modulators but do not seem to contribute to specificity. Mutations in two others (␣3Leu107 and ␣3Ile117) yielded receptors with appreciable ␣4-character; that is, Mor potentiation was reduced compared with wild-type ␣3␤2 control and Oxa inhibition was evident. A fifth position (␣3Glu113) was unique in that it discriminated between the two compounds, showing no change in Mor potentiation from control but substantial Oxa inhibition. Our work has implications for rational drug design for nicotinic receptors and sheds light on mechanisms of allosteric modulation in nAChRs, especially the subtle differences between potentiation and inhibition.

H3.3 Nucleosome Assembly Mutants Display a Late-Onset Maternal Effect Highlights d Loss of H3.3 assembly factors results in late-onset defects d Mitochondrial stress likely contributes to these late-onset defects d The late-onset defects of H3.3 assembly mutants can be maternally rescued