Regulation of Cortico-Thalamic JNK1/2 and ERK1/2 MAPKs and Apoptosis-Related Signaling Pathways in PDYN Gene-Deficient Mice Following Acute and Chronic Mild Stress

This article belongs to the Special Issue Involvement of the MAPK Pathway in Cancer and Immunology.
The crosstalk between the opioidergic system and mitogen-activated protein kinases (MAPKs) has a critical role in mediating stress-induced behaviors related to the pathophysiology of anxiety. The present study evaluated the basal status and stress-induced alterations of cortico-thalamic MAPKs and other cell fate-related signaling pathways potentially underlying the anxiogenic endophenotype of PDYN gene-deficient mice. Compared to littermates, PDYN knockout (KO) mice had lower cortical and or thalamic amounts of the phospho-activated MAPKs c-Jun N-terminal kinase (JNK1/2) and extracellular signal-regulated kinase (ERK1/2). Similarly, PDYN-KO animals displayed reduced cortico-thalamic densities of total and phosphorylated (at Ser191) species of the cell fate regulator Fas-associated protein with death domain (FADD) without alterations in the Fas receptor. Exposure to acute restraint and chronic mild stress stimuli induced the robust stimulation of JNK1/2 and ERK1/2 MAPKs, FADD, and Akt-mTOR pathways, without apparent increases in apoptotic rates. Interestingly, PDYN deficiency prevented stress-induced JNK1/2 and FADD but not ERK1/2 or Akt-mTOR hyperactivations. These findings suggest that cortico-thalamic MAPK- and FADD-dependent neuroplasticity might be altered in PDYN-KO mice. In addition, the results also indicate that the PDYN gene (and hence dynorphin release) may be required to stimulate JNK1/2 and FADD (but not ERK1/2 or Akt/mTOR) pathways under environmental stress conditions.
This joint research was funded by Red Temática de Investigación Cooperativa en Salud–Red de Trastornos Adictivos (RETICS–RTA, Instituto de Salud Carlos III [ISCIII], MCIU/AEI/FEDER), Grupos RD06/0001/0004 (J.M.) and RD06/0001/0003 (J.A.G.-S.). J.M. also received financial support from Proyectos de Investigación en Salud—ISCIII (grant RD. PI18/00576), Red de Investigación en Atención Primaria de Adicciones (grant RD21/0009/0008), and Delegación del Gobierno para el Plan Nacional Sobre Drogas (PNSD, grant 2019I012) from the Spanish Ministry of Health (MSC). This study was also supported by MCIU/AEI/FEDER (grants RTI2018-094414-A-I00 to A.R.-M., PID2019-109323RA-I00 to T.F., and SAF2008-01311 to J.A.G.-S.), and MSC/FEDER (FIS 05/0429 to J.M). A.R.-M. (grant RYC-2016-19282) and T.F. (grant RYC-2017-22666) are ‘Ramón y Cajal’ Researchers.