Pyk2 in the amygdala modulates chronic stress sequelae via PSD-95-related micro-structural changes

Transl Psychiatry. 2019 Jan 15;9(1):3. doi: 10.1038/s41398-018-0352-y.


Major depressive disorder (MDD) is a common disorder with a variety of symptoms including mood alterations, anhedonia, sleep and appetite disorders, and cognitive disturbances. Stressful life events are among the strongest risk factors for developing MDD. At the cellular level, chronic stress results in the modification of dendritic spine morphology and density. Here, we study the role of Pyk2 in the development of depressive-like symptoms induced by a model of chronic unpredictable mild stress (CUMS). Pyk2 is a non-receptor calcium-dependent protein-tyrosine kinase highly expressed in the forebrain principal neurons and involved in spine structure and density regulation. We show that Pyk2 knockout mice are less affected to anxiety-like and anhedonia-like phenotypes induced by the CUMS paradigm. Using region-specific knockout, we demonstrate that this phenotype is fully recapitulated by selective Pyk2 inactivation in the amygdala. We also show that in the absence of Pyk2 the spine alterations, PSD-95 clustering, and NMDA receptors changes induced by the CUMS paradigm are prevented. Our results reveal a possible role for Pyk2 in the response to stress and in synaptic markers expression and spine density regulation in the amygdala. We suggest that Pyk2 contributes to stress-induced responses through micro-structural changes and that its deficit may contribute to the resilience to chronic stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / metabolism*
  • Animals
  • Behavior, Animal
  • Dendritic Spines / metabolism
  • Depressive Disorder, Major / etiology
  • Depressive Disorder, Major / metabolism*
  • Disease Models, Animal
  • Disks Large Homolog 4 Protein / metabolism*
  • Focal Adhesion Kinase 2 / genetics
  • Focal Adhesion Kinase 2 / metabolism*
  • Mice
  • Mice, Knockout
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Stress, Psychological / metabolism*


  • Disks Large Homolog 4 Protein
  • Receptors, N-Methyl-D-Aspartate
  • Focal Adhesion Kinase 2
  • Ptk2b protein, mouse