TY - JOUR
T1 - Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory
AU - Okuda, Kosuke
AU - Takao, Keizo
AU - Watanabe, Aya
AU - Miyakawa, Tsuyoshi
AU - Mizuguchi, Masashi
AU - Tanaka, Teruyuki
N1 - Funding Information:
This work was supported by Grants-in-Aid for Scientific Research 21659252, 23500381, 15K09614 (TT, MM) and Research Fellowship for Young Scientists 12J04298 (KO) from Japan Society for the Promotion of Science (http://www.jsps.go.jp/english/), Grants-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) (TT, KO, KT, TM) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (http://www.mext.go.jp/en/), Comprehensive Research on Disability Health and Welfare (Neurological and Muscle diseases) Grant 24-007 of the Ministry of Health, Labor and Welfare of Japan (http://www.mhlw.go.jp/english/) (TT), research grants from The Japan Epilepsy Research Foundation (http://www.epi-fj.jp) (TT), The Mother and Child Health Foundation (http://www.glico.co.jp/boshi/) (TT), and Japan Rett Syndrome Support Organization (http://www.nporett.jp) (TT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank J. R. Sanes (Harvard University) for the Thy1-EGFP transgenic mice, and C. Tohyama (The University of Tokyo) for the use of Neurolucida software.
PY - 2018/4
Y1 - 2018/4
N2 - Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-con-taining N-methyl-D-aspartate (NMDA) receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles. The neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, one-chamber and three-chamber social interaction, 24-h home cage monitoring, contextual and cued fear conditioning, Barnes maze, and T-maze tests were applied on adult Cdkl5 -/Y and +/Y mice. Cdkl5 -/Y mice showed a mild alteration in the gait. Analyses of emotional behaviors revealed significantly enhanced anxiety-like behaviors of Cdkl5 -/Y mice. Depressive-like behaviors and social interaction of Cdkl5 -/Y mice were uniquely altered. The contextual and cued fear conditioning of Cdkl5 -/Y mice were comparable to control mice; however, Cdkl5 -/Y mice showed a significantly increased freezing time and a significantly decreased distance traveled during the pretone period in the altered context. Both acquisition and long-term retention of spatial reference memory were significantly impaired. The morphometric analysis of hippocampal CA1 pyramidal neurons revealed impaired dendritic arborization and immature spine development in Cdkl5 -/Y mice. These results indicate that CDKL5 plays significant roles in regulating emotional behaviors especially on anxiety- and fear-related responses, and in both acquisition and long-term retention of spatial reference memory, which suggests that focus and special attention should be paid to the specific mechanisms of these deficits in the CDKL5 deficiency disorder.
AB - Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-con-taining N-methyl-D-aspartate (NMDA) receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles. The neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, one-chamber and three-chamber social interaction, 24-h home cage monitoring, contextual and cued fear conditioning, Barnes maze, and T-maze tests were applied on adult Cdkl5 -/Y and +/Y mice. Cdkl5 -/Y mice showed a mild alteration in the gait. Analyses of emotional behaviors revealed significantly enhanced anxiety-like behaviors of Cdkl5 -/Y mice. Depressive-like behaviors and social interaction of Cdkl5 -/Y mice were uniquely altered. The contextual and cued fear conditioning of Cdkl5 -/Y mice were comparable to control mice; however, Cdkl5 -/Y mice showed a significantly increased freezing time and a significantly decreased distance traveled during the pretone period in the altered context. Both acquisition and long-term retention of spatial reference memory were significantly impaired. The morphometric analysis of hippocampal CA1 pyramidal neurons revealed impaired dendritic arborization and immature spine development in Cdkl5 -/Y mice. These results indicate that CDKL5 plays significant roles in regulating emotional behaviors especially on anxiety- and fear-related responses, and in both acquisition and long-term retention of spatial reference memory, which suggests that focus and special attention should be paid to the specific mechanisms of these deficits in the CDKL5 deficiency disorder.
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U2 - 10.1371/journal.pone.0196587
DO - 10.1371/journal.pone.0196587
M3 - Article
C2 - 29702698
AN - SCOPUS:85046089847
VL - 13
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 4
M1 - e0196587
ER -