Selectively Impaired Endocannabinoid-Dependent Long-Term Depression in the Lateral Habenula in an Animal Model of Depression

Cell Rep. 2017 Jul 11;20(2):289-296. doi: 10.1016/j.celrep.2017.06.049.


Abnormal potentiation in the lateral habenula (LHb) has been suggested to mediate depression-like behaviors. However, the underlying mechanisms of the synaptic efficacy regulation of LHb synapses and the potential for their modulation are only poorly understood. Here, we report that long-term synaptic depression (LTD) occurs in the LHb upon both low-frequency stimulation (LFS) and moderate-frequency stimulation (MFS). LFS-induced LTD (LFS-LTD) is accompanied by a reduction in presynaptic release probability, which is endocannabinoid (eCB) signaling dependent. Surprisingly, exposure to an acute stressor completely masks the induction of LFS-LTD in the LHb while leaving the MFS-induced LTD intact. Pharmacological activation of cannabinoid receptor 1 (CB1R) or blockade of αCaMKII successfully restored LTD in the LHb in an animal model of depression. Thus, our findings reveal a form of synaptic strength regulation and a stress-induced shift of synaptic plasticity in the LHb.

Keywords: depressive disorders; endocannabinoids; lateral habenula; long-term depression; synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Depression / metabolism*
  • Depression / pathology*
  • Disease Models, Animal
  • Electrophysiology
  • Endocannabinoids / metabolism*
  • Habenula / metabolism*
  • Habenula / pathology*
  • Long-Term Synaptic Depression / physiology*
  • Male
  • Neuronal Plasticity / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Real-Time Polymerase Chain Reaction


  • Endocannabinoids