Serotonin (5-HT) neuron-specific inactivation of Cadherin-13 impacts 5-HT system formation and cognitive function

NEUROPHARMACOLOGY

卷:168

Article

Forero, Andrea¹  Ku, Hsing-Ping¹  Malpartida, Ana Belen¹  Waeldchen, Sina²  Alhama-Riba, Judit¹  Kulka, Christina¹  Aboagye, Benjamin¹  Norton, William H. J.³  Young, Andrew M. J.³  Ding, Yu-Qiang⁴  Blum, Robert⁵  Sauer, Markus²  Rivero, Olga¹  Lesch, Klaus-Peter^1,6,7 

[1] Univ Wurzburg, Ctr Mental Hlth, Div Mol Psychiat, Margarete Hoppel Pl 1, D-97080 Wurzburg, Germany

[2] Univ Wurzburg, Bioctr, Dept Biotechnol & Biophys, Wurzburg, Germany

[3] Univ Leicester, Dept Neurosci Psychol & Behav, Leicester, Leics, England

[4] Fudan Univ, Inst Brain Sci, Shanghai 200031, Peoples R China

[5] Univ Wurzburg, Inst Clin Neurobiol, Wurzburg, Germany

[6] Sechenov First Moscow State Med Univ, Inst Mol Med, Lab Psychiat Neurobiol, Moscow, Russia

[7] Maastricht Univ, Sch Mental Hlth & Neurosci MHeNS, Dept Psychiat & Neuropsychol, Maastricht, Netherlands

关键词: Serotonin (5-HT);    Raphe nucleus;    Cadherin-13;    Cell adhesion molecules;    Neurodevelopment;    Learning and memory;   

DOI  :  10.1016/j.neuropharm.2020.108018

来源: Elsevier

【 摘 要 】

Genome-wide screening approaches identified the cell adhesion molecule Cadherin-13 (CDH13) as a risk factor for neurodevelopmental disorders, nevertheless the contribution of CDH13 to the disease mechanism remains obscure. CDH13 is involved in neurite outgrowth and axon guidance during early brain development and we previously provided evidence that constitutive CDH13 deficiency influences the formation of the raphe serotonin (5-HT) system by modifying neuron-radial glia interaction. Here, we dissect the specific impact of CDH13 on 5-HT system development and function using a 5-HT neuron-specific Cdh13 knockout mouse model (conditional Cdh13 knockout, Cdh13 cKO). Our results show that exclusive inactivation of CDH13 in 5-HT neurons selectively increases 5-HT neuron density in the embryonic dorsal raphe, with persistence into adulthood, and serotonergic innervation of the developing prefrontal cortex. At the behavioral level, adult Cdh13 cKO mice display delayed acquisition of several learning tasks and a subtle impulsive-like phenotype, with decreased latency in a sociability paradigm alongside with deficits in visuospatial memory. Anxiety-related traits were not observed in Cdh13 cKO mice. Our findings further support the critical role of CDH13 in the development of dorsal raphe 5-HT circuitries, a mechanism that may underlie specific clinical features observed in neurodevelopmental disorders.

【 授权许可】

Free