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

Andrea Forero; Hsing-Ping Ku; Ana Belen Malpartida; Sina Waeldchen; Judit Alhama-Riba; Christina Kulka; Benjamin Aboagye; William H. J. Norton; Andrew M. J. Young; Yu-Qiang Ding; Robert Blum; Markus Sauer; Olga Rivero; Klaus-Peter Lesch

doi:10.1016/j.neuropharm.2020.108018

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

Andrea Forero^*, Hsing-Ping Ku, Ana Belen Malpartida, Sina Waeldchen, Judit Alhama-Riba, Christina Kulka, Benjamin Aboagye, William H. J. Norton, Andrew M. J. Young, Yu-Qiang Ding, Robert Blum, Markus Sauer, Olga Rivero, Klaus-Peter Lesch^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Article number	108018
Number of pages	14
Journal	Neuropharmacology
Volume	168
DOIs	https://doi.org/10.1016/j.neuropharm.2020.108018
Publication status	Published - 15 May 2020

Keywords

Serotonin (5-HT)
Raphe nucleus
Cadherin-13
Cell adhesion molecules
Neurodevelopment
Learning and memory
T-CADHERIN
CORTEX
DEFICIENCY
MODULATION
DOPAMINE
PATHWAY
REGIONS
GENES
MICE

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Forero, A., Ku, H.-P., Malpartida, A. B., Waeldchen, S., Alhama-Riba, J., Kulka, C., Aboagye, B., Norton, W. H. J., Young, A. M. J., Ding, Y.-Q., Blum, R., Sauer, M., Rivero, O., & Lesch, K.-P. (2020). Serotonin (5-HT) neuron-specific inactivation of Cadherin-13 impacts 5-HT system formation and cognitive function. Neuropharmacology, 168, Article 108018. https://doi.org/10.1016/j.neuropharm.2020.108018

@article{827f987a05be49b6a5aed4cc9cb77a79,

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

abstract = "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.",

keywords = "Serotonin (5-HT), Raphe nucleus, Cadherin-13, Cell adhesion molecules, Neurodevelopment, Learning and memory, T-CADHERIN, CORTEX, DEFICIENCY, MODULATION, DOPAMINE, PATHWAY, REGIONS, GENES, MICE",

author = "Andrea Forero and Hsing-Ping Ku and Malpartida, {Ana Belen} and Sina Waeldchen and Judit Alhama-Riba and Christina Kulka and Benjamin Aboagye and Norton, {William H. J.} and Young, {Andrew M. J.} and Yu-Qiang Ding and Robert Blum and Markus Sauer and Olga Rivero and Klaus-Peter Lesch",

note = "Funding Information: We gratefully recognize the excellent technical assistance of G. Ortega y Schulte, N. Steigerwald, and A. Dietzel. We also thank C. R{\"u}dt von Collenberg for her support with the laser-capture microdissection method. 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 W{\"u}rzburg. The funding entities had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2020 The Authors",

year = "2020",

month = may,

day = "15",

doi = "10.1016/j.neuropharm.2020.108018",

language = "English",

volume = "168",

journal = "Neuropharmacology",

issn = "0028-3908",

publisher = "Elsevier Science",

}

Forero, A, Ku, H-P, Malpartida, AB, Waeldchen, S, Alhama-Riba, J, Kulka, C, Aboagye, B, Norton, WHJ, Young, AMJ, Ding, Y-Q, Blum, R, Sauer, M, Rivero, O & Lesch, K-P 2020, 'Serotonin (5-HT) neuron-specific inactivation of Cadherin-13 impacts 5-HT system formation and cognitive function', Neuropharmacology, vol. 168, 108018. https://doi.org/10.1016/j.neuropharm.2020.108018

TY - JOUR

T1 - Serotonin (5-HT) neuron-specific inactivation of Cadherin-13 impacts 5-HT system formation and cognitive function

AU - Forero, Andrea

AU - Ku, Hsing-Ping

AU - Malpartida, Ana Belen

AU - Waeldchen, Sina

AU - Alhama-Riba, Judit

AU - Kulka, Christina

AU - Aboagye, Benjamin

AU - Norton, William H. J.

AU - Young, Andrew M. J.

AU - Ding, Yu-Qiang

AU - Blum, Robert

AU - Sauer, Markus

AU - Rivero, Olga

AU - Lesch, Klaus-Peter

N1 - Funding Information: We gratefully recognize the excellent technical assistance of G. Ortega y Schulte, N. Steigerwald, and A. Dietzel. We also thank C. Rüdt von Collenberg for her support with the laser-capture microdissection method. 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. The funding entities had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: © 2020 The Authors

PY - 2020/5/15

Y1 - 2020/5/15

N2 - 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.

AB - 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.

KW - Serotonin (5-HT)

KW - Raphe nucleus

KW - Cadherin-13

KW - Cell adhesion molecules

KW - Neurodevelopment

KW - Learning and memory

KW - T-CADHERIN

KW - CORTEX

KW - DEFICIENCY

KW - MODULATION

KW - DOPAMINE

KW - PATHWAY

KW - REGIONS

KW - GENES

KW - MICE

U2 - 10.1016/j.neuropharm.2020.108018

DO - 10.1016/j.neuropharm.2020.108018

M3 - Article

C2 - 32113967

SN - 0028-3908

VL - 168

JO - Neuropharmacology

JF - Neuropharmacology

M1 - 108018

ER -