Circadian and homeostatic regulation of structural synaptic plasticity in hypocretin neurons

Lior Appelbaum, Gordon Wang, Tohei Yokogawa, Gemini M. Skariah, Stephen J. Smith, Philippe Mourrain, Emmanuel Mignot

Research output: Contribution to journalArticlepeer-review

131 Scopus citations


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.

Original languageEnglish
Pages (from-to)87-98
Number of pages12
Issue number1
StatePublished - 6 Oct 2010

Bibliographical note

Funding Information:
We thank Laura Alexandere and Wilfredo Marin for assistance in fish maintenance and experiments. We thank Dr. Géraldine Maro for her expertise and assistance in confocal microscopy. We also thank Dr. Jamie Zeitzer and Dr. Oren levy for helping in statistical analysis and Dr. Matthew E. Carter, Dr. Brian Grone, Dr. Juliette Faraco, Dr. Simon Warby, Dr. Yoav Gothilf, and Dr. Luis de Lecea for helpful comments on the manuscript. This research was supported by the McKnight Foundation, the NIH (NS23724, NS062798), the Howard Hughes Medical Research Institute (E.M.), and the Vincent Coates Foundation (S.J.S.).


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