Comprehensive behavioral analysis of mice deficient in Rapgef2 and Rapgef6, a subfamily of guanine nucleotide exchange factors for Rap small GTPases possessing the Ras/Rap-associating domain.
Rapgef2 and Rapgef6 define a subfamily of guanine nucleotide exchange factors for Rap small GTPases, characterized by the possession of the Ras/Rap-associating domain. Previous genomic analyses suggested their possible involvement in the etiology of schizophrenia. We recently demonstrated the development of an ectopic cortical mass (ECM), which resembles the human subcortical band heterotopia, in the dorsal telencephalon-specific Rapgef2 conditional knockout (Rapgef2-cKO) brains. Additional knockout of Rapgef6 in Rapgef2-cKO mice resulted in gross enlargement of the ECM whereas knockout of Rapgef6 alone (Rapgef6-KO) had no discernible effect on the brain morphology. Here, we performed a battery of behavioral tests to examine the effects of Rapgef2 or Rapgef6 deficiency on higher brain functions. Rapgef2-cKO mice exhibited hyperlocomotion phenotypes. They showed decreased anxiety-like behavior in the elevated plus maze and the open-field tests as well as increased depression-like behavior in the Porsolt forced swim and tail suspension tests. They also exhibited increased sociability especially in novel environments. They showed defects in cognitive function as evidenced by reduced learning ability in the Barnes circular maze test and by impaired working memory in the T maze tests. In contrast, although Rapgef6 and Rapgef2 share similarities in biochemical roles, Rapgef6-KO mice exhibited mild behavioral abnormalities detected with a number of behavioral tests, such as hyperlocomotion phenotype in the open-field test and the social interaction test with a novel environment and working-memory defects in the T-maze test. In conclusion, although there were differences in their brain morphology and the magnitude of the behavioral abnormalities, Rapgef2-cKO mice and Rapgef6-KO mice exhibited hyperlocomotion phenotype and working-memory defect, both of which could be recognized as schizophrenia-like behavior.
['Maeta|Kazuhiro|K|', 'Hattori|Satoko|S|', 'Ikutomo|Junji|J|', 'Edamatsu|Hironori|H|', 'Bilasy|Shymaa E|SE|', 'Miyakawa|Tsuyoshi|T|', 'Kataoka|Tohru|T|']
D000818:Animals D001007:Anxiety D001522:Behavior, Animal D003071:Cognition D003213:Conditioning, Psychological D003863:Depression D005239:Fear D020662:Guanine Nucleotide Exchange Factors D018782:Maze Learning D008568:Memory D018345:Mice, Knockout D009043:Motor Activity D065808:Prepulse Inhibition D000072417:Protein Domains D013216:Reflex, Startle D012919:Social Behavior
Behavioral analysis Rapgef2 Rapgef6 Guanine nucleotide exchange factors Rap small GTPases Schizophrenia