Published Online:https://doi.org/10.1152/jn.00383.2017

We studied the changes in sensitivity to a peptide modulator, crustacean cardioactive peptide (CCAP), as a response to loss of endogenous modulation in the stomatogastric ganglion (STG) of the crab Cancer borealis. Our data demonstrate that removal of endogenous modulation for 24 h increases the response of the lateral pyloric (LP) neuron of the STG to exogenously applied CCAP. Increased responsiveness is accompanied by increases in CCAP receptor (CCAPr) mRNA levels in LP neurons, requires de novo protein synthesis, and can be prevented by coincubation for the 24-h period with exogenous CCAP. These results suggest that there is a direct feedback from loss of CCAP signaling to the production of CCAPr that increases subsequent response to the ligand. However, we also demonstrate that the modulator-evoked membrane current (IMI) activated by CCAP is greater in magnitude after combined loss of endogenous modulation and activity compared with removal of just hormonal modulation. These results suggest that both receptor expression and an increase in the target conductance of the CCAP G protein-coupled receptor are involved in the increased response to exogenous hormone exposure following experimental loss of modulation in the STG.

NEW & NOTEWORTHY The nervous system shows a tremendous amount of plasticity. More recently there has been an appreciation for compensatory actions that stabilize output in the face of perturbations to normal activity. In this study we demonstrate that neurons of the crustacean stomatogastric ganglion generate apparent compensatory responses to loss of peptide neuromodulation, adding to the repertoire of mechanisms by which the stomatogastric nervous system can regulate and stabilize its own output.

REFERENCES

  • Billimoria CP, Li L, Marder E. Profiling of neuropeptides released at the stomatogastric ganglion of the crab, Cancer borealis with mass spectrometry. J Neurochem 95: 191–199, 2005. doi:10.1111/j.1471-4159.2005.03355.x.
    Crossref | PubMed | Web of Science | Google Scholar
  • Blitz DM, Beenhakker MP, Nusbaum MP. Different sensory systems share projection neurons but elicit distinct motor patterns. J Neurosci 24: 11381–11390, 2004. doi:10.1523/JNEUROSCI.3219-04.2004.
    Crossref | PubMed | Web of Science | Google Scholar
  • Brown G. The actions of acetylcholine on denervated mammalian frog’s muscle. J Physiol 89: 438–461, 1937. doi:10.1113/jphysiol.1937.sp003491.
    Crossref | PubMed | Google Scholar
  • Bucher D, Marder E. SnapShot: Neuromodulation. Cell 155: 482–482.e1, 2013. doi:10.1016/j.cell.2013.09.047.
    Crossref | PubMed | Google Scholar
  • Cai G, Wang HY, Friedman E. Increased dopamine receptor signaling and dopamine receptor-G protein coupling in denervated striatum. J Pharmacol Exp Ther 302: 1105–1112, 2002. doi:10.1124/jpet.102.036673.
    Crossref | PubMed | Web of Science | Google Scholar
  • Cannon W, Rosenblueth A. The Supersensitivity of Denervated Structures. New York: Macmillan, 1949.
    Google Scholar
  • Chen R, Ma M, Hui L, Zhang J, Li L. Measurement of neuropeptides in crustacean hemolymph via MALDI mass spectrometry. J Am Soc Mass Spectrom 20: 708–718, 2009. doi:10.1016/j.jasms.2008.12.007.
    Crossref | PubMed | Web of Science | Google Scholar
  • Christie AE, Chi M, Lameyer TJ, Pascual MG, Shea DN, Stanhope ME, Schulz DJ, Dickinson PS. Neuropeptidergic signaling in the American lobster Homarus americanus: new insights from high-throughput nucleotide sequencing. PLoS One 10: e0145964, 2015. doi:10.1371/journal.pone.0145964.
    Crossref | PubMed | Web of Science | Google Scholar
  • Christie AE, Skiebe P, Marder E. Matrix of neuromodulators in neurosecretory structures of the crab Cancer borealis. J Exp Biol 198: 2431–2439, 1995.
    Crossref | PubMed | Web of Science | Google Scholar
  • Christie AE, Stemmler EA, Dickinson PS. Crustacean neuropeptides. Cell Mol Life Sci 67: 4135–4169, 2010. doi:10.1007/s00018-010-0482-8.
    Crossref | PubMed | Web of Science | Google Scholar
  • Civelli O. Orphan GPCRs and neuromodulation. Neuron 76: 12–21, 2012. doi:10.1016/j.neuron.2012.09.009.
    Crossref | PubMed | Web of Science | Google Scholar
  • Daur N, Nadim F, Bucher D. The complexity of small circuits: the stomatogastric nervous system. Curr Opin Neurobiol 41: 1–7, 2016. doi:10.1016/j.conb.2016.07.005.
    Crossref | PubMed | Web of Science | Google Scholar
  • DeLong ND, Kirby MS, Blitz DM, Nusbaum MP. Parallel regulation of a modulator-activated current via distinct dynamics underlies comodulation of motor circuit output. J Neurosci 29: 12355–12367, 2009. doi:10.1523/JNEUROSCI.3079-09.2009.
    Crossref | PubMed | Web of Science | Google Scholar
  • Garcia VJ, Daur N, Temporal S, Schulz DJ, Bucher D. Neuropeptide receptor transcript expression levels and magnitude of ionic current responses show cell type-specific differences in a small motor circuit. J Neurosci 35: 6786–6800, 2015. doi:10.1523/JNEUROSCI.0171-15.2015.
    Crossref | PubMed | Web of Science | Google Scholar
  • Gasselin C, Inglebert Y, Debanne D. Homeostatic regulation of h-conductance controls intrinsic excitability and stabilizes the threshold for synaptic modification in CA1 neurons. J Physiol 593: 4855–4869, 2015. doi:10.1113/JP271369.
    Crossref | PubMed | Web of Science | Google Scholar
  • Golowasch J, Marder E. Proctolin activates an inward current whose voltage dependence is modified by extracellular Ca2+. J Neurosci 12: 810–817, 1992.
    Crossref | PubMed | Web of Science | Google Scholar
  • Hamood AW, Haddad SA, Otopalik AG, Rosenbaum P, Marder E. Quantitative reevaluation of the effects of short- and long-term removal of descending modulatory inputs on the pyloric rhythm of the crab, Cancer borealis. eNeuro 2: 1–25, 2015. doi:10.1523/ENEURO.0058-14.2015.
    Crossref | PubMed | Web of Science | Google Scholar
  • Han DW, Patel N, Watson RD. Regulation of protein synthesis in Y-organs of the blue crab (Callinectes sapidus): involvement of cyclic AMP. J Exp Zool A Comp Exp Biol 305: 328–334, 2006. doi:10.1002/jez.a.263.
    Crossref | PubMed | Google Scholar
  • Harris-Warrick RM. Neuromodulation and flexibility in central pattern generator networks. Curr Opin Neurobiol 21: 685–692, 2011. doi:10.1016/j.conb.2011.05.011.
    Crossref | PubMed | Web of Science | Google Scholar
  • Hazell GG, Hindmarch CC, Pope GR, Roper JA, Lightman SL, Murphy D, O’Carroll AM, Lolait SJ. G protein-coupled receptors in the hypothalamic paraventricular and supraoptic nuclei—serpentine gateways to neuroendocrine homeostasis. Front Neuroendocrinol 33: 45–66, 2012. doi:10.1016/j.yfrne.2011.07.002.
    Crossref | PubMed | Web of Science | Google Scholar
  • Hedrich UB, Smarandache CR, Stein W. Differential activation of projection neurons by two sensory pathways contributes to motor pattern selection. J Neurophysiol 102: 2866–2879, 2009. doi:10.1152/jn.00618.2009.
    Link | Web of Science | Google Scholar
  • Husch A, Van Patten GN, Hong DN, Scaperotti MM, Cramer N, Harris-Warrick RM. Spinal cord injury induces serotonin supersensitivity without increasing intrinsic excitability of mouse V2a interneurons. J Neurosci 32: 13145–13154, 2012. doi:10.1523/JNEUROSCI.2995-12.2012.
    Crossref | PubMed | Web of Science | Google Scholar
  • Ibata K, Sun Q, Turrigiano GG. Rapid synaptic scaling induced by changes in postsynaptic firing. Neuron 57: 819–826, 2008. doi:10.1016/j.neuron.2008.02.031.
    Crossref | PubMed | Web of Science | Google Scholar
  • Khorkova O, Golowasch J. Neuromodulators, not activity, control coordinated expression of ionic currents. J Neurosci 27: 8709–8718, 2007. doi:10.1523/JNEUROSCI.1274-07.2007.
    Crossref | PubMed | Web of Science | Google Scholar
  • Ko PK, Anderson MJ, Cohen MW. Denervated skeletal muscle fibers develop discrete patches of high acetylcholine receptor density. Science 196: 540–542, 1977.
    Crossref | PubMed | Web of Science | Google Scholar
  • Krenz WD, Hooper RM, Parker AR, Prinz AA, Baro DJ. Activation of high and low affinity dopamine receptors generates a closed loop that maintains a conductance ratio and its activity correlate. Front Neural Circuits 7: 169, 2013. doi:10.3389/fncir.2013.00169.
    Crossref | PubMed | Web of Science | Google Scholar
  • Krenz WD, Parker AR, Rodgers EW, Baro DJ. Dopaminergic tone persistently regulates voltage-gated ion current densities through the D1R-PKA axis, RNA polymerase II transcription, RNAi, mTORC1, and translation. Front Cell Neurosci 8: 39, 2014. doi:10.3389/fncel.2014.00039.
    Crossref | PubMed | Web of Science | Google Scholar
  • Krenz WD, Rodgers EW, Baro DJ. Tonic 5 nM DA stabilizes neuronal output by enabling bidirectional activity-dependent regulation of the hyperpolarization activated current via PKA and calcineurin. PLoS One 10: e0117965, 2015. doi:10.1371/journal.pone.0117965.
    Crossref | PubMed | Web of Science | Google Scholar
  • Kvarta MD, Harris-Warrick RM, Johnson BR. Neuromodulator-evoked synaptic metaplasticity within a central pattern generator network. J Neurophysiol 108: 2846–2856, 2012. doi:10.1152/jn.00586.2012.
    Link | Web of Science | Google Scholar
  • Lee KF, Soares C, Béïque JC. Tuning into diversity of homeostatic synaptic plasticity. Neuropharmacology 78: 31–37, 2014. doi:10.1016/j.neuropharm.2013.03.016.
    Crossref | PubMed | Web of Science | Google Scholar
  • Li L, Kelley WP, Billimoria CP, Christie AE, Pulver SR, Sweedler JV, Marder E. Mass spectrometric investigation of the neuropeptide complement and release in the pericardial organs of the crab, Cancer borealis. J Neurochem 87: 642–656, 2003. doi:10.1046/j.1471-4159.2003.02031.x.
    Crossref | PubMed | Web of Science | Google Scholar
  • Maffei A, Turrigiano GG. Multiple modes of network homeostasis in visual cortical layer 2/3. J Neurosci 28: 4377–4384, 2008. doi:10.1523/JNEUROSCI.5298-07.2008.
    Crossref | PubMed | Web of Science | Google Scholar
  • Marder E, Bucher D. Understanding circuit dynamics using the stomatogastric nervous system of lobsters and crabs. Annu Rev Physiol 69: 291–316, 2007. doi:10.1146/annurev.physiol.69.031905.161516.
    Crossref | PubMed | Web of Science | Google Scholar
  • Marder E, Eisen JS. Electrically coupled pacemaker neurons respond differently to same physiological inputs and neurotransmitters. J Neurophysiol 51: 1362–1374, 1984.
    Link | Web of Science | Google Scholar
  • Maynard DM, Dando MR. The structure of the stomatogastric neuromuscular system in Callinectes sapidus, Homarus americanus and Panulirus argus (Decapoda Crustacea). Philos Trans R Soc Lond B Biol Sci 268: 161–220, 1974. doi:10.1098/rstb.1974.0024.
    Crossref | PubMed | Web of Science | Google Scholar
  • Miller JP, Selverston AI. Mechanisms underlying pattern generation in lobster stomatogastric ganglion as determined by selective inactivation of identified neurons. II. Oscillatory properties of pyloric neurons. J Neurophysiol 48: 1378–1391, 1982.
    Link | Web of Science | Google Scholar
  • Nadim F, Bucher D. Neuromodulation of neurons and synapses. Curr Opin Neurobiol 29: 48–56, 2014. doi:10.1016/j.conb.2014.05.003.
    Crossref | PubMed | Web of Science | Google Scholar
  • Nahar J, Lett KM, Schulz DJ. Restoration of descending inputs fails to rescue activity following deafferentation of a motor network. J Neurophysiol 108: 871–881, 2012. doi:10.1152/jn.00183.2012.
    Link | Web of Science | Google Scholar
  • Nicholls JG. The electrical properties of denervated skeletal muscle. J Physiol 131: 1–12, 1956. doi:10.1113/jphysiol.1956.sp005440.
    Crossref | PubMed | Web of Science | Google Scholar
  • Northcutt AJ, Lett KM, Garcia VB, Diester CM, Lane BJ, Marder E, Schulz DJ. Deep sequencing of transcriptomes from the nervous systems of two decapod crustaceans to characterize genes important for neural circuit function and modulation. BMC Genomics 17: 868, 2016. doi:10.1186/s12864-016-3215-z.
    Crossref | PubMed | Web of Science | Google Scholar
  • Ransdell JL, Faust TB, Schulz DJ. Correlated levels of mRNA and soma size in single identified neurons: evidence for compartment-specific regulation of gene expression. Front Mol Neurosci 3: 116, 2010. doi:10.3389/fnmol.2010.00116.
    Crossref | PubMed | Web of Science | Google Scholar
  • Rodgers EW, Fu JJ, Krenz WD, Baro DJ. Tonic nanomolar dopamine enables an activity-dependent phase recovery mechanism that persistently alters the maximal conductance of the hyperpolarization-activated current in a rhythmically active neuron. J Neurosci 31: 16387–16397, 2011a. doi:10.1523/JNEUROSCI.3770-11.2011.
    Crossref | PubMed | Web of Science | Google Scholar
  • Rodgers EW, Krenz WD, Jiang X, Li L, Baro DJ. Dopaminergic tone regulates transient potassium current maximal conductance through a translational mechanism requiring D1Rs, cAMP/PKA, Erk and mTOR. BMC Neurosci 14: 143, 2013. doi:10.1186/1471-2202-14-143.
    Crossref | PubMed | Web of Science | Google Scholar
  • Rodgers EW, Krenz WD, Baro DJ. Tonic dopamine induces persistent changes in the transient potassium current through translational regulation. J Neurosci 31: 13046–13056, 2011b. doi:10.1523/JNEUROSCI.2194-11.2011.
    Crossref | PubMed | Web of Science | Google Scholar
  • Schulz DJ. Plasticity and stability in neuronal output via changes in intrinsic excitability: it’s what’s inside that counts. J Exp Biol 209: 4821–4827, 2006. doi:10.1242/jeb.02567.
    Crossref | PubMed | Web of Science | Google Scholar
  • Schulz DJ, Lane BJ. Homeostatic plasticity of excitability in crustacean central pattern generator networks. Curr Opin Neurobiol 43: 7–14, 2017. doi:10.1016/j.conb.2016.09.015.
    Crossref | PubMed | Web of Science | Google Scholar
  • Staunton DA, Magistretti PJ, Koob GF, Shoemaker WJ, Bloom FE. Dopaminergic supersensitivity induced by denervation and chronic receptor blockade is additive. Nature 299: 72–74, 1982. doi:10.1038/299072a0.
    Crossref | PubMed | Web of Science | Google Scholar
  • Stein W. Modulation of stomatogastric rhythms. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 195: 989–1009, 2009. doi:10.1007/s00359-009-0483-y.
    Crossref | PubMed | Web of Science | Google Scholar
  • Swensen AM, Marder E. Multiple peptides converge to activate the same voltage-dependent current in a central pattern-generating circuit. J Neurosci 20: 6752–6759, 2000.
    Crossref | PubMed | Web of Science | Google Scholar
  • Swensen AM, Marder E. Modulators with convergent cellular actions elicit distinct circuit outputs. J Neurosci 21: 4050–4058, 2001.
    Crossref | PubMed | Web of Science | Google Scholar
  • Temporal S, Desai M, Khorkova O, Varghese G, Dai A, Schulz DJ, Golowasch J. Neuromodulation independently determines correlated channel expression and conductance levels in motor neurons of the stomatogastric ganglion. J Neurophysiol 107: 718–727, 2012. doi:10.1152/jn.00622.2011.
    Link | Web of Science | Google Scholar
  • Temporal S, Lett KM, Schulz DJ. Activity-dependent feedback regulates correlated ion channel mRNA levels in single identified motor neurons. Curr Biol 24: 1899–1904, 2014. doi:10.1016/j.cub.2014.06.067.
    Crossref | PubMed | Web of Science | Google Scholar
  • Thoby-Brisson M, Simmers J. Neuromodulatory inputs maintain expression of a lobster motor pattern-generating network in a modulation-dependent state: evidence from long-term decentralization in vitro. J Neurosci 18: 2212–2225, 1998.
    Crossref | PubMed | Web of Science | Google Scholar
  • Thoby-Brisson M, Simmers J. Transition to endogenous bursting after long-term decentralization requires de novo transcription in a critical time window. J Neurophysiol 84: 596–599, 2000.
    Link | Web of Science | Google Scholar
  • Thoby-Brisson M, Simmers J. Long-term neuromodulatory regulation of a motor pattern-generating network: maintenance of synaptic efficacy and oscillatory properties. J Neurophysiol 88: 2942–2953, 2002. doi:10.1152/jn.00482.2001.
    Link | Web of Science | Google Scholar
  • Turrigiano G. Homeostatic synaptic plasticity: local and global mechanisms for stabilizing neuronal function. Cold Spring Harb Perspect Biol 4: a005736, 2012. doi:10.1101/cshperspect.a005736.
    Crossref | PubMed | Web of Science | Google Scholar
  • Turrigiano GG. The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135: 422–435, 2008. doi:10.1016/j.cell.2008.10.008.
    Crossref | PubMed | Web of Science | Google Scholar
  • Weimann JM, Skiebe P, Heinzel HG, Soto C, Kopell N, Jorge-Rivera JC, Marder E. Modulation of oscillator interactions in the crab stomatogastric ganglion by crustacean cardioactive peptide. J Neurosci 17: 1748–1760, 1997.
    Crossref | PubMed | Web of Science | Google Scholar