Academic Appointments

All Publications

  • Synaptic plasticity in sleep: learning, homeostasis and disease TRENDS IN NEUROSCIENCES Wang, G., Grone, B., Colas, D., Appelbaum, L., Mourrain, P. 2011; 34 (9): 452-463


    Sleep is a fundamental and evolutionarily conserved aspect of animal life. Recent studies have shed light on the role of sleep in synaptic plasticity. Demonstrations of memory replay and synapse homeostasis suggest that one essential role of sleep is in the consolidation and optimization of synaptic circuits to retain salient memory traces despite the noise of daily experience. Here, we review this recent evidence and suggest that sleep creates a heightened state of plasticity, which may be essential for this optimization. Furthermore, we discuss how sleep deficits seen in diseases such as Alzheimer's disease and autism spectrum disorders might not just reflect underlying circuit malfunction, but could also play a direct role in the progression of those disorders.

    View details for DOI 10.1016/j.tins.2011.07.005

    View details for Web of Science ID 000294941300002

    View details for PubMedID 21840068

    View details for PubMedCentralID PMC3385863

  • Circadian and Homeostatic Regulation of Structural Synaptic Plasticity in Hypocretin Neurons NEURON Appelbaum, L., Wang, G., Yokogawa, T., Skariah, G. M., Smith, S. J., Mourrain, P., Mignot, E. 2010; 68 (1): 87-98


    Neurons exhibit rhythmic activity that ultimately affects behavior such as sleep. In living zebrafish larvae, we used time-lapse two-photon imaging of the presynaptic marker synaptophysin in hypocretin/orexin (HCRT) neurons to determine the dynamics of synaptic modifications during the day and night. We observed circadian rhythmicity in synapse number in HCRT axons. This rhythm is regulated primarily by the circadian clock but is also affected by sleep deprivation. Furthermore, NPTX2, a protein implicated in AMPA receptor clustering, modulates circadian synaptic changes. In zebrafish, nptx2b is a rhythmic gene that is mostly expressed in hypothalamic and pineal gland cells. Arrhythmic transgenic nptx2b overexpression (hcrt:NPTX2b) increases synapse number and abolishes rhythmicity in HCRT axons. Finally, hcrt:NPTX2b fish are resistant to the sleep-promoting effects of melatonin. This behavioral effect is consistent with NPTX2b-mediated increased activity of HCRT circuitry. These data provide real-time in vivo evidence of circadian and homeostatic regulation of structural synaptic plasticity.

    View details for DOI 10.1016/j.neuron.2010.09.006

    View details for Web of Science ID 000283704200010

    View details for PubMedID 20920793

    View details for PubMedCentralID PMC2969179

  • Sleep-wake regulation and hypocretin-melatonin interaction in zebrafish PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Appelbaum, L., Wang, G. X., Maro, G. S., Mori, R., Tovin, A., Marin, W., Yokogawa, T., Kawakami, K., Smith, S. J., Gothilf, Y., Mignot, E., Mourrain, P. 2009; 106 (51): 21942-21947


    In mammals, hypocretin/orexin (HCRT) neuropeptides are important sleep-wake regulators and HCRT deficiency causes narcolepsy. In addition to fragmented wakefulness, narcoleptic mammals also display sleep fragmentation, a less understood phenotype recapitulated in the zebrafish HCRT receptor mutant (hcrtr-/-). We therefore used zebrafish to study the potential mediators of HCRT-mediated sleep consolidation. Similar to mammals, zebrafish HCRT neurons express vesicular glutamate transporters indicating conservation of the excitatory phenotype. Visualization of the entire HCRT circuit in zebrafish stably expressing hcrt:EGFP revealed parallels with established mammalian HCRT neuroanatomy, including projections to the pineal gland, where hcrtr mRNA is expressed. As pineal-produced melatonin is a major sleep-inducing hormone in zebrafish, we further studied how the HCRT and melatonin systems interact functionally. mRNA level of arylalkylamine-N-acetyltransferase (AANAT2), a key enzyme of melatonin synthesis, is reduced in hcrtr-/- pineal gland during the night. Moreover, HCRT perfusion of cultured zebrafish pineal glands induces melatonin release. Together these data indicate that HCRT can modulate melatonin production at night. Furthermore, hcrtr-/- fish are hypersensitive to melatonin, but not other hypnotic compounds. Subthreshold doses of melatonin increased the amount of sleep and consolidated sleep in hcrtr-/- fish, but not in the wild-type siblings. These results demonstrate the existence of a functional HCRT neurons-pineal gland circuit able to modulate melatonin production and sleep consolidation.

    View details for DOI 10.1073/pnas.906637106

    View details for Web of Science ID 000272994200086

    View details for PubMedID 19966231

    View details for PubMedCentralID PMC2799794

  • Requirement of TRPC channels in netrin-1-induced chemotropic turning of nerve growth cones NATURE Wang, G. X., Poo, M. M. 2005; 434 (7035): 898-904


    Ion channels formed by the TRP (transient receptor potential) superfamily of proteins act as sensors for temperature, osmolarity, mechanical stress and taste. The growth cones of developing axons are responsible for sensing extracellular guidance factors, many of which trigger Ca2+ influx at the growth cone; however, the identity of the ion channels involved remains to be clarified. Here, we report that TRP-like channel activity exists in the growth cones of cultured Xenopus neurons and can be modulated by exposure to netrin-1 and brain-derived neurotrophic factor, two chemoattractants for axon guidance. Whole-cell recording from growth cones showed that netrin-1 induced a membrane depolarization, part of which remained after all major voltage-dependent channels were blocked. Furthermore, the membrane depolarization was sensitive to blockers of TRP channels. Pharmacological blockade of putative TRP currents or downregulation of Xenopus TRP-1 (xTRPC1) expression with a specific morpholino oligonucleotide abolished the growth-cone turning and Ca2+ elevation induced by a netrin-1 gradient. Thus, TRPC currents reflect early events in the growth cone's detection of some extracellular guidance signals, resulting in membrane depolarization and cytoplasmic Ca2+ elevation that mediates the turning of growth cones.

    View details for DOI 10.1038/nature03478

    View details for Web of Science ID 000228327600041

    View details for PubMedID 15758951