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Gabaergic Synaptic Plasticity During a Developmentally Regulated Sleep-Like State in C

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Gabaergic Synaptic Plasticity During a Developmentally Regulated Sleep-Like State in C 15932 • The Journal of Neuroscience, November 2, 2011 • 31(44):15932–15943 Development/Plasticity/Repair GABAergic Synaptic Plasticity during a Developmentally Regulated Sleep-Like State in C. elegans Nooreen S. Dabbish and David M. Raizen Department of Neurology and Center for Sleep and Circadian Neurobiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19014 Approximately one-fourth of the neurons in Caenorhabditis elegans adults are born during larval development, indicating tremendous plasticity in larval nervous system structure. Larval development shows cyclical expression of sleep-like quiescent behavior during lethargus periods, which occur at larval stage transitions. We studied plasticity at the neuromuscular junction during lethargus using the acetylcholinesterase inhibitor aldicarb. The rate of animal contraction when exposed to aldicarb is controlled by the balance between excitatory cholinergic and inhibitory GABAergic input on the muscle. During lethargus, there is an accelerated rate of contraction on aldicarb. Mutant analysis and optogenetic studies reveal that GABAergic synaptic transmission is reduced during lethargus. Worms in lethargus show partial resistance to GABAA receptor agonists, indicating that postsynaptic mechanisms contribute to lethargus- dependent plasticity. Using genetic manipulations that separate the quiescent state from the developmental stage, we show that the synaptic plasticity is dependent on developmental time and not on the behavioral state of the animal. We propose that the synaptic plasticity regulated by a developmental clock in C. elegans is analogous to synaptic plasticity regulated by the circadian clock in other species. Introduction time (Ferna´ndez et al., 2008). At the Drosophila NMJ, there are Nervous system remodeling is an ancient, widespread phe- circadian changes in the size of MN terminals (Mehnert et al., nomenon seen in animals ranging from cnidarians to verte- 2007). Zebrafish display circadian changes in the number of pre- brates (Nakanishi et al., 2008; Watanabe et al., 2009). During synaptic boutons in hypocretin neurons. In addition, there is a developmental transitions, holometabolous insects—those that small effect of the sleep/wake behavioral state on synaptic plastic- undergo a complete metamorphosis—show profound remodel- ity in the hypocretin neuron terminals (Appelbaum et al., 2010). ing (Tissot and Stocker, 2000). At the insect neuromuscular junc- In Drosophila subjected to sleep deprivation, increases in levels of tion (NMJ), adult motoneurons (MNs) remodel from larval both presynaptic and postsynaptic proteins (Gilestro et al., 2009) precursors (Levine and Truman, 1982). Both the muscle and the and an increase in the number of synaptic terminals in clock MNs reorganize at the NMJ, and this reorganization is dependent neurons (Donlea et al., 2009) suggest that synaptic plasticity is on signaling through steroid hormones (Hegstrom and Truman, also influenced by the animal’s behavioral state (sleep vs wake). 1996). In Drosophila, synapse elimination begins with postsynap- To further explore the molecular and genetic underpinnings tic dismantling of the NMJ (Liu et al., 2010b). of synaptic change in a system that captures developmental, Remodeling occurs not only as a function of nervous system clock-like, and sleep/wake features, we chose to examine synaptic development, but also as a function of circadian clock and sleep/ transmission during Caenorhabditis elegans larval development. wake cycles. In Drosophila, remodeling of pigment-dispersing Development from embryo to reproductive adulthood in C. el- factor-positive neurons is observed as a function of circadian egans is punctuated by four molts, which separate the four larval stages from each other and the fourth larval stage from the adult Received Feb. 10, 2011; revised Sept. 9, 2011; accepted Sept. 19, 2011. stage. At the end of each larval stage, there is a stage called leth- Author contributions: N.S.D. and D.M.R. designed research; N.S.D. and D.M.R. performed research; N.S.D. and argus. Lethargus is a behaviorally quiescent period characterized D.M.R. analyzed data; N.S.D. and D.M.R. wrote the paper. D.M.R. is supported by R01 NS064030-01A1 and by a National Alliance for Research on Schizophrenia and by the sleep-like properties of reversibility, increased arousal Depression(NARSAD)YoungInvestigatorAward.N.S.D.issupportedbyT32HL07953.WearegratefultoJean-Louis threshold, and homeostasis (Raizen et al., 2008). In addition, Bessereauforthegiftofanti-UNC-49antibodiesandfordetailedstainingprotocols.WethankErikJorgensen,Cheryl lethargus timing is coupled to the expression of lin-42, the C. Van Buskirk, and the C. elegans Genetics Center (which is funded by the NIH National Center for Research Resources) elegans ortholog of the circadian protein PERIOD (Jeon et al., forprovidingstrainsandJazzPharmaceuticalforprovidingsodiumoxybate.WethankAnnesiaLamb,RobertDriver, andKunHeLeefortechnicalassistance.Forcommentsonthismanuscript,wethankMattNelson,NickTrojanowski, 1999). Therefore, larval development in C. elegans captures ele- Sarah McLoughlin, and Todd Lamitina. ments of both developmental clock-controlled changes and be- The authors declare no competing financial interests. havioral state-controlled changes. Correspondence should be addressed to David M. Raizen Department of Neurology, Perelman School of To study the mechanisms of synaptic alterations during leth- Medicine at the University of Pennsylvania, 464 Stemmler, 415 Curie Boulevard, Philadelphia, PA 19014. argus, we used pharmacological and optogenetic approaches to E-mail: [email protected]. DOI:10.1523/JNEUROSCI.0742-11.2011 examine synaptic transmission at the NMJ. We show that synap- Copyright © 2011 the authors 0270-6474/11/3115932-12$15.00/0 tic transmission is altered during lethargus periods. We found Dabbish and Raizen • Synaptic Plasticity in C. elegans Lethargus J. Neurosci., November 2, 2011 • 31(44):15932–15943 • 15933 that this alteration occurs during lethargus but not during other worms became less mobile they were aligned in the center of the plate to quiescent behavioral states. During lethargus, there is a reduction facilitate rapid observation of the worms at that time point. in transmission at GABAergic synapses at the body wall NMJ. We Aldicarb sensitivity of satiety worms and their controls was assessed on further show that this reduction can be explained in part by a aldicarb plates fully seeded with the bacteria HB101. The assessments of change in the GABAergic synapse’s postsynaptic function. aldicarb sensitivity and satiety behavior were done blind to prior treat- ment of the worms (satiety-inducing conditions vs controls). Satiety behavior was induced by the starvation refeeding method as described Materials and Methods previously (You et al., 2008). Satiated worms showed a delayed latency to General methods and strains. Worms were cultured and handled as described resumption of movement and feeding (20.8 Ϯ 5.5 s) relative to control previously (Brenner, 1974). All experiments were performed on hermaph- well fed worms (4.6 Ϯ 4.7 s) (p ϭ 0.0001). rodites. Unless otherwise noted, worms were grown at 20°C on NGM agar The LIN-3 heat shock aldicarb assay was performed blinded to condi- plates supplemented with streptomycin sulfate at 50 ␮g/ml and fed the strep- tion (with or without heat shock). Worms were heat shocked by immers- tomycin-resistant Escherichia coli strain DA837 (Davis et al., 1995). C. elegans ing the agar plate housing them in a water bath set to 33°C for 30 min. The Variety Bristol strain N2 was used as the wild-type strain. Strains used were aldicarb assay was started 2 h after the end of the heat shock. We found IB16 ceh-17(np1) I, JT1734 goa-1(sa734) I, CB156 unc-25(e156) III, CB407 that the heat shock reproduced the behavioral effects (cessation of pump- unc-49(e407) III, CB382 unc-49(e382)III, FK234 egl-4(ks62) IV, DA521 egl- ing and locomotion) reported for LIN-3 overexpression (Van Buskirk 4(ad450) IV, NM1968 slo-1( js379) V, CB6055 bus-8(e2698) X, MH1955 and Sternberg, 2007). nhr-25(ku217) X, PS5009 pha-1(e2132ts) III;him-5(e1490) V;syEx723 Pentylenetetrazole assay. Pentylenetetrazole (PTZ; Sigma catalog no. [hs::LIN-3C;Pmyo2:GFP;pha-1(ϩ)], EG5025 [Punc-47:ChR2::mCherry], P6500) was included in the NGM at a concentration of 5 mg/ml as and EG5096 [Punc-17:ChR2::mCherry]. described previously (Locke et al., 2009). These plates were seeded with The transgenes Punc-17:ChR2::mCherry and Punc-47:ChR2::mCherry the bacteria DA837. Plates containing PTZ were stored overnight at 4°C. were crossed into unc-25 and into goa-1 mutants by isolating from heterozy- Mid-L4, lethargus, and adult worms were plated on the PTZ plates pre- gotes progeny that showed the Unc-25 and Goa-1 phenotypes, respectively, warmed to room temperature and then observed at 15, 30, and 60 min. At and also showed red fluorescence. Homozygosity of the transgene was then each of these time points, worm behavior was categorized as follows: (1) confirmed by looking for 100% progeny with red fluorescence. normal crawling behavior; (2) posterior paralysis; (3) complete paralysis; RNA interference (RNAi) experiments to knock down nhr-23 were and (4) convulsions (also referred to as “head bobs”) (Williams et al., performed by the feeding method (Timmons and Fire, 1998) using bac- 2004; Locke et al., 2009). In this assay, paralyzed worms were neither teria expressing nhr-23 genomic
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