Collagen VI Regulates Motor Circuit Plasticity and Motor Performance by Cannabinoid Modulation

Daniel D. Lam, Rhîannan H. Williams, Ernesto Lujan, Koji Tanabe, Georg Huber, Nay Lui Saw, Juliane Merl-Pham, Aaro V. Salminen, David Lohse, Sally Spendiff, Melanie J. Plastini, Michael Zech, Hanns Lochmüller, Arie Geerlof, Stefanie M. Hauck, Mehrdad Shamloo, Marius Wernig, Juliane Winkelmann

Research output: Contribution to journalArticlepeer-review


Collagen VI is a key component of muscle basement membranes, and genetic variants can cause monogenic muscular dystrophies. Conversely, human genetic studies recently implicated collagen VI in central nervous system function, with variants causing the movement disorder dystonia. To elucidate the neurophysiological role of collagen VI, we generated mice with a truncation of the dystonia-related collagen a3 VI (COL6A3) C-terminal domain (CTD). These Col6a3CTT mice showed a recessive dystonia-like phenotype in both sexes. We found that COL6A3 interacts with the cannabinoid receptor 1 (CB1R) complex in a CTD-dependent manner. Col6a3CTT mice of both sexes have impaired homeostasis of excitatory input to the basal pontine nuclei (BPN), a motor control hub with dense COL6A3 expression, consistent with deficient endocannabinoid (eCB) signaling. Aberrant synaptic input in the BPN was normalized by a CB1R agonist, and motor performance in Col6a3CTT mice of both sexes was improved by CB1R agonist treatment. Our findings identify a readily therapeutically addressable synaptic mechanism for motor control.

Original languageEnglish
Pages (from-to)1557-1573
Number of pages17
JournalJournal of Neuroscience
Issue number8
StatePublished - 23 Feb 2022


  • basal pontine nuclei
  • cannabinoid receptor
  • collagen VI
  • dystonia
  • endocannabinoid
  • synaptic homeostasis


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