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

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 A.G. is a Ramón y Cajal fellow (RYC-2016-19466). This work was supported by the NARSAD foundation (young investigator grant 2016 (Ref. 24803) to A.G.) and Ministerio de Ciencia e Innovació n (SAF2015-67474-R; MINECO/FEDER to S.G.). J.-A.G. lab was supported in part by Inserm, the Université Pierre et Marie Curie (UPMC, Sorbonne Université), the Fondation pour la Recherche Médicale, and the Bio-Psy (Biology for Psychiatry) laboratory of excellence. O.A.-M. was funded by the ISCIII/SERGAS thought a research contract “Sara Borrell” (CD14/ 00091). JA lab was supported by the Spanish Ministry of Economy and Competitiveness (MINECO) (SAF-2014-57160R, SAF-2017-88076-R), Fundació Marató TV3 to J.A. and Instituto Carlos III: Centro de Investigación Biomédica en Red sobre enfermedades neurodegenerativas (CIBERNED), and RETICS RD12/ 0019/0002 to J.A.) SI