Lack of striatal-enriched protein tyrosine phosphatase STEP affected serotonin system, behavior, and brain morphology in mice

Vitalii Sergeevich Moskaliuk^1*Polina Dmitrievna Komleva¹Nikita Valerievich Khotskin¹Alla Borisovna Arefieva¹Oleg Borisovich Shevelev^1,2Alexey Nikolaevich Korablev^1,3Nariman Rashitovich Battulin¹Irina Alexandrovna Serova¹Alexander Viktorovich Kulikov¹Vladimir Sergeevich Naumenko¹Darya Vladimirovna Bazovkina¹Elizabeth Alexandrovna Kulikova¹

• ¹Institute of Cytology and Genetics, Russian Academy of Sciences (RAS), Novosibirsk, Russia
• ²Nacional'nyj issledovatel'skij Tomskij politehniceskij universitet, Tomsk, Russia
• ³State Research Center of Virology and Biotechnology "Vector", Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being, Koltsovo, Russia

Introduction: Mental disorders are a severe problem of modern society. Significant in these conditions are the striatal-enriched protein tyrosine phosphatase STEP (Ptpn5 gene) and the serotonergic system. Nevertheless, the association between them is poorly studied. The aim of this research was to investigate the effects of Ptpn5 gene knockout on behavior and serotonin system in mice. Methods: Utilizing the CRISPR/Cas9 system we cleaved the PTP-domain-encoding sequence from the Ptpn5 gene of C57BL/6 mice. The resulting strain (Ptpn5 KO) demonstrated STEP protein absence and ERK1/2 hyperphosphorylation (STEP substrate) in the brain. We performed behavioral phenotyping, structural MRI and biomolecular screening of the serotonergic system. Results: Ptpn5 KO mice resembled the wild type in locomotor activity, motor function, and social behavior. They were overactive during dark hours, showed reduced anxiety-related behavior, elevated grooming activity, and an increased pre-pulse inhibition index. Mutant mice performed poorly in the water-related tests. They demonstrated higher immobility time in the forced swim test but not in the analogous dry tail suspension test, and exhibited troubles finding the platform in the Morris water maze but did not fail the novel object recognition test or the operant wall task. Therefore, the observed differences may be a reaction to environmental stress rather than depressive-like behavior or learning deficiency. The Ptpn5 KO strain had a bigger cortex and striatum but a smaller midbrain and cerebellum. Serotonin and its metabolite content was lower in the frontal cortex and higher in the midbrain of Ptpn5 KO mice. A lack of STEP elevated TPH2 protein level in the hippocampus, and reduced Htr1a and Htr7 mRNA expression in the midbrain and hippocampus, respectively. Discussion: The data obtained in this study indicate a significant role of STEP in the regulation of behavior and brain architecture, and highlight the connection between STEP and the 5-HT system.