Activation of the 5-HT7 receptor and MMP-9 signaling module in the hippocampal CA1 region is necessary for the development of depressive-like behavior

Cell Rep. 2022 Mar 15;38(11):110532. doi: 10.1016/j.celrep.2022.110532.

Abstract

Major depressive disorder is a complex disease resulting from aberrant synaptic plasticity that may be caused by abnormal serotonergic signaling. Using a combination of behavioral, biochemical, and imaging methods, we analyze 5-HT7R/MMP-9 signaling and dendritic spine plasticity in the hippocampus in mice treated with the selective 5-HT7R agonist (LP-211) and in a model of chronic unpredictable stress (CUS)-induced depressive-like behavior. We show that acute 5-HT7R activation induces depressive-like behavior in mice in an MMP-9-dependent manner and that post mortem brain samples from human individuals with depression reveal increased MMP-9 enzymatic activity in the hippocampus. Both pharmacological activation of 5-HT7R and modulation of its downstream effectors as a result of CUS lead to dendritic spine elongation and decreased spine density in this region. Overall, the 5-HT7R/MMP-9 pathway is specifically activated in the CA1 subregion of the hippocampus during chronic stress and is crucial for inducing depressive-like behavior.

Keywords: 5-HT7R; CDC42; CP: Neuroscience; LP-211; MDD; MMP-9; anhedonia; chronic unpredictable stress; dendritic spines; depressive-like behavior; synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CA1 Region, Hippocampal* / metabolism
  • Depressive Disorder, Major* / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Receptors, Serotonin / metabolism

Substances

  • Receptors, Serotonin
  • serotonin 7 receptor
  • Matrix Metalloproteinase 9