Hippocampal Pyk2 regulates specific social skills: Implications for schizophrenia

• Published in: Neurobiology of disease Vol. 194; p. 106487
• Main Authors: López-Molina, Laura, Sancho-Balsells, Anna, Al-Massadi, Omar, Montalban, Enrica, Alberch, Jordi, Arranz, Belén, Girault, Jean-Antoine, Giralt, Albert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2024; Elsevier
• Subjects: Animals; Focal Adhesion Kinase 2 - metabolism; Hippocampus; Hippocampus - metabolism; Humans; Life Sciences; Mice; Psychosis; Pyramidal Cells - metabolism; Schizophrenia; Social Skills; Social symptoms; Psychosis; Social symptoms; Hippocampus
• ISSN: 0969-9961; 1095-953X; 1095-953X
• DOI: 10.1016/j.nbd.2024.106487

Pyk2 has been shown previously to be involved in several psychological and cognitive alterations related to stress, Huntington's disease, and Alzheimer's disease. All these disorders are accompanied by different types of impairments in sociability, which has recently been linked to improper mitochondrial function. We hypothesize that Pyk2, which regulates mitochondria, could be associated with the regulation of mitochondrial dynamics and social skills. In the present manuscript, we report that a reduction of Pyk2 levels in mouse pyramidal neurons of the hippocampus decreased social dominance and aggressivity. Furthermore, social interactions induced robust Pyk2-dependent hippocampal changes in several oxidative phosphorylation complexes. We also observed that Pyk2 levels were increased in the CA1 pyramidal neurons of schizophrenic subjects, occurring alongside changes in different direct and indirect regulators of mitochondrial function including DISC1 and Grp75. Accordingly, overexpressing Pyk2 in hippocampal CA1 pyramidal cells mimicked some specific schizophrenia-like social behaviors in mice. In summary, our results indicate that Pyk2 might play a role in regulating specific social skills likely via mitochondrial dynamics and that there might be a link between Pyk2 levels in hippocampal neurons and social disturbances in schizophrenia. •Hippocampal Pyk2 in pyramidal neurons is essential for the proper regulation of social dominance and aggressiveness.•Pyk2 regulates some mitochondrial protein levels and activation during social interaction.•Pyk2 levels in hippocampal pyramidal neurons are increased in schizophrenic patients.•Overexpressing Pyk2 in hippocampal pyramidal neurons mimics some schizophrenic-like social deficits in mice.