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Serotonin (5-HT) neuron-specific inactivation.pdf (9.38 MB)

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

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journal contribution
posted on 2021-07-05, 22:00 authored by Andrea Forero, Hsing-Ping Ku, Ana Belen Malpartida, Sina Waeldchen, Judit Alhama-Riba, Christina Kulka, Benjamin Aboagye, William HJ Norton, Andrew MJ Young, Yu-Qiang Ding, Robert Blum, Markus Sauer, Olga Rivero, Klaus-Peter Lesch
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.

Funding

This work was supported by Deutsche Forschungsgemeinschaft (DFG: SFB TRR 58/A5, to KPL), the European Union's Seventh Framework Programme (FP7/2007–2013) under Grant No. 602805 (Aggressotype), the Horizon 2020 Research and Innovation Programme under Grant No. 728018 (Eat2beNICE) and Grant No. 643051 (MiND), ERA-Net NEURON/RESPOND, No. 01EW1602B, ERA-Net NEURON/ DECODE, No. 01EW1902 (to KPL and OR) and 5–100 Russian Academic Excellence Project (to KPL). AF was supported by a grant of the German Excellence Initiative to the Graduate School of Life Sciences (GSLS), University of Würzburg.

History

Citation

Neuropharmacology 168 (2020) 108018

Author affiliation

Department of Neuroscience, Psychology and Behaviou

Version

  • VoR (Version of Record)

Published in

Neuropharmacology

Volume

168

Publisher

Elsevier

issn

0028-3908

eissn

1873-7064

Acceptance date

2020-02-23

Copyright date

2020

Available date

2021-07-05

Spatial coverage

England

Language

English