Dissociation of impulsivity and aggression in mice deficient for the ADHD risk gene Adgrl3: Evidence for dopamine transporter dysregulation

Niall Mortimer; Tatjana Ganster; Aet O'Leary; Sandy Popp; Florian Freudenberg; Andreas Reif; Maria Soler Artigas; Marta Ribases; Josep Antoni Ramos-Quiroga; Klaus-Peter Lesch; Olga Rivero

doi:10.1016/j.neuropharm.2019.02.039

Dissociation of impulsivity and aggression in mice deficient for the ADHD risk gene Adgrl3: Evidence for dopamine transporter dysregulation

Niall Mortimer, Tatjana Ganster, Aet O'Leary, Sandy Popp, Florian Freudenberg, Andreas Reif, Maria Soler Artigas, Marta Ribases, Josep Antoni Ramos-Quiroga, Klaus-Peter Lesch, Olga Rivero^*

^*Corresponding author for this work

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

Abstract

Adhesion G protein-coupled receptor L3 (ADGRL3, LPHN3) has putative roles in neuronal migration and synapse function. Various polymorphisms in ADGRL3 have been linked with an increased risk of attention deficit/hyperactivity disorder (ADHD). In this study, we examined the characteristics of Adgrl3-deficient mice in multiple behavioural domains related to ADHD: locomotive activity, impulsivity, gait, visuospatial and recognition memory, sociability, anxiety-like behaviour and aggression. Additionally, we investigated the effect of Adgrl3-depletion at the transcriptomic level by RNA-sequencing three ADHD-relevant brain regions: prefrontal cortex (PFC), hippocampus and striatum.

Adgrl3(-/-) mice show increased locomotive activity across all tests and subtle gait abnormalities. These mice also show impairments across spatial memory and learning domains, alongside increased levels of impulsivity and sociability with decreased aggression. However, these alterations were absent in Adgrl3(-/-) mice. Across all brain regions tested, the numbers of genes found to exhibit differential expression was relatively small, indicating a specific pathway of action, rather than a broad neurobiological perturbation. Gene-set analysis of differential expression in the PFC detected a number of ADHD-relevant pathways including dopaminergic synapses as well as cocaine and amphetamine addiction. The Slc6a3 gene coding for the dopamine transporter was the most dysregulated gene in the PFC. Unexpectedly, several neurohormone/peptides which are typically only expressed in the hypothamalus were found to be dysregulated in the striatum. Our study further validates Adgrl3 constitutive knockout mice as an experimental model of ADHD while providing neuroanatomical targets for future studies involving ADGRL3 modified models.

This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.

Original language	English
Article number	107557
Number of pages	17
Journal	Neuropharmacology
Volume	156
DOIs	https://doi.org/10.1016/j.neuropharm.2019.02.039
Publication status	Published - 15 Sept 2019

Keywords

AMYGDALA MORPHOLOGY
ANIMAL-MODEL
ATTENTION-DEFICIT/HYPERACTIVITY DISORDER
Adhesion G protein-coupled receptor L3 (ADGRL3)
Attention-deficit/hyperactivity disorder (ADHD)
CHILDREN
GAIT
GENOME-WIDE ASSOCIATION
Hippocampus
LPHN3
Latrophilin
Latrophilin 3 (LPHN3)
METHYLPHENIDATE
Mouse model
NEUROTRANSMISSION
PREFRONTAL CORTEX
Prefrontal cortex
Striatum
SUSCEPTIBILITY
HIPPOCAMPUS

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10.1016/j.neuropharm.2019.02.039

Cite this

Mortimer, N., Ganster, T., O'Leary, A., Popp, S., Freudenberg, F., Reif, A., Soler Artigas, M., Ribases, M., Antoni Ramos-Quiroga, J., Lesch, K.-P., & Rivero, O. (2019). Dissociation of impulsivity and aggression in mice deficient for the ADHD risk gene Adgrl3: Evidence for dopamine transporter dysregulation. Neuropharmacology, 156, Article 107557. https://doi.org/10.1016/j.neuropharm.2019.02.039

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title = "Dissociation of impulsivity and aggression in mice deficient for the ADHD risk gene Adgrl3: Evidence for dopamine transporter dysregulation",

abstract = "Adhesion G protein-coupled receptor L3 (ADGRL3, LPHN3) has putative roles in neuronal migration and synapse function. Various polymorphisms in ADGRL3 have been linked with an increased risk of attention deficit/hyperactivity disorder (ADHD). In this study, we examined the characteristics of Adgrl3-deficient mice in multiple behavioural domains related to ADHD: locomotive activity, impulsivity, gait, visuospatial and recognition memory, sociability, anxiety-like behaviour and aggression. Additionally, we investigated the effect of Adgrl3-depletion at the transcriptomic level by RNA-sequencing three ADHD-relevant brain regions: prefrontal cortex (PFC), hippocampus and striatum.Adgrl3(-/-) mice show increased locomotive activity across all tests and subtle gait abnormalities. These mice also show impairments across spatial memory and learning domains, alongside increased levels of impulsivity and sociability with decreased aggression. However, these alterations were absent in Adgrl3(-/-) mice. Across all brain regions tested, the numbers of genes found to exhibit differential expression was relatively small, indicating a specific pathway of action, rather than a broad neurobiological perturbation. Gene-set analysis of differential expression in the PFC detected a number of ADHD-relevant pathways including dopaminergic synapses as well as cocaine and amphetamine addiction. The Slc6a3 gene coding for the dopamine transporter was the most dysregulated gene in the PFC. Unexpectedly, several neurohormone/peptides which are typically only expressed in the hypothamalus were found to be dysregulated in the striatum. Our study further validates Adgrl3 constitutive knockout mice as an experimental model of ADHD while providing neuroanatomical targets for future studies involving ADGRL3 modified models.This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.",

keywords = "AMYGDALA MORPHOLOGY, ANIMAL-MODEL, ATTENTION-DEFICIT/HYPERACTIVITY DISORDER, Adhesion G protein-coupled receptor L3 (ADGRL3), Attention-deficit/hyperactivity disorder (ADHD), CHILDREN, GAIT, GENOME-WIDE ASSOCIATION, Hippocampus, LPHN3, Latrophilin, Latrophilin 3 (LPHN3), METHYLPHENIDATE, Mouse model, NEUROTRANSMISSION, PREFRONTAL CORTEX, Prefrontal cortex, Striatum, SUSCEPTIBILITY, HIPPOCAMPUS",

author = "Niall Mortimer and Tatjana Ganster and Aet O'Leary and Sandy Popp and Florian Freudenberg and Andreas Reif and {Soler Artigas}, Maria and Marta Ribases and {Antoni Ramos-Quiroga}, Josep and Klaus-Peter Lesch and Olga Rivero",

note = "Funding Information: We are grateful to G. Ortega y Schulte, A. Dietzel and M. Gunzel for excellent technical assistance. This work was supported by Deutsche Forschungsgemeinschaft (SFB TRR 58/A5 to KPL; RTG 1253 to KPL), the European Commission (EC: AGGRESSOTYPE FP7/No. 602805 to KPL, OR, and AR; MiND/No. 643051 to KPL and AR; COCA/No. 667302 to AR), Fritz Thyssen Foundation (Az. 10.13.1185 to KPL) and 5-100 Russian Academic Excellence Project (to KPL). NM was supported by MiND Marie Sklodowska-Curie which received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no 643051, while TG was supported by a grant of the German Excellence Initiative to the Graduate School of Life Sciences (GSLS), University of W?rzburg. The funding entities had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding Information: We are grateful to G. Ortega y Schulte, A. Dietzel and M. Gunzel for excellent technical assistance. This work was supported by Deutsche Forschungsgemeinschaft (SFB TRR 58/A5 to KPL; RTG 1253 to KPL), the European Commission (EC: AGGRESSOTYPE FP7/No. 602805 to KPL, OR, and AR; MiND /No. 643051 to KPL and AR; COCA /No. 667302 to AR), Fritz Thyssen Foundation (Az. 10.13.1185 to KPL) and 5-100 Russian Academic Excellence Project (to KPL). NM was supported by MiND Marie Sklodowska-Curie which received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no 643051 , while TG 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} 2019 Elsevier Ltd",

year = "2019",

month = sep,

day = "15",

doi = "10.1016/j.neuropharm.2019.02.039",

language = "English",

volume = "156",

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Mortimer, N, Ganster, T, O'Leary, A, Popp, S, Freudenberg, F, Reif, A, Soler Artigas, M, Ribases, M, Antoni Ramos-Quiroga, J, Lesch, K-P & Rivero, O 2019, 'Dissociation of impulsivity and aggression in mice deficient for the ADHD risk gene Adgrl3: Evidence for dopamine transporter dysregulation', Neuropharmacology, vol. 156, 107557. https://doi.org/10.1016/j.neuropharm.2019.02.039

TY - JOUR

T1 - Dissociation of impulsivity and aggression in mice deficient for the ADHD risk gene Adgrl3

T2 - Evidence for dopamine transporter dysregulation

AU - Mortimer, Niall

AU - Ganster, Tatjana

AU - O'Leary, Aet

AU - Popp, Sandy

AU - Freudenberg, Florian

AU - Reif, Andreas

AU - Soler Artigas, Maria

AU - Ribases, Marta

AU - Antoni Ramos-Quiroga, Josep

AU - Lesch, Klaus-Peter

AU - Rivero, Olga

N1 - Funding Information: We are grateful to G. Ortega y Schulte, A. Dietzel and M. Gunzel for excellent technical assistance. This work was supported by Deutsche Forschungsgemeinschaft (SFB TRR 58/A5 to KPL; RTG 1253 to KPL), the European Commission (EC: AGGRESSOTYPE FP7/No. 602805 to KPL, OR, and AR; MiND/No. 643051 to KPL and AR; COCA/No. 667302 to AR), Fritz Thyssen Foundation (Az. 10.13.1185 to KPL) and 5-100 Russian Academic Excellence Project (to KPL). NM was supported by MiND Marie Sklodowska-Curie which received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no 643051, while TG was supported by a grant of the German Excellence Initiative to the Graduate School of Life Sciences (GSLS), University of W?rzburg. The funding entities had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding Information: We are grateful to G. Ortega y Schulte, A. Dietzel and M. Gunzel for excellent technical assistance. This work was supported by Deutsche Forschungsgemeinschaft (SFB TRR 58/A5 to KPL; RTG 1253 to KPL), the European Commission (EC: AGGRESSOTYPE FP7/No. 602805 to KPL, OR, and AR; MiND /No. 643051 to KPL and AR; COCA /No. 667302 to AR), Fritz Thyssen Foundation (Az. 10.13.1185 to KPL) and 5-100 Russian Academic Excellence Project (to KPL). NM was supported by MiND Marie Sklodowska-Curie which received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no 643051 , while TG 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: © 2019 Elsevier Ltd

PY - 2019/9/15

Y1 - 2019/9/15

N2 - Adhesion G protein-coupled receptor L3 (ADGRL3, LPHN3) has putative roles in neuronal migration and synapse function. Various polymorphisms in ADGRL3 have been linked with an increased risk of attention deficit/hyperactivity disorder (ADHD). In this study, we examined the characteristics of Adgrl3-deficient mice in multiple behavioural domains related to ADHD: locomotive activity, impulsivity, gait, visuospatial and recognition memory, sociability, anxiety-like behaviour and aggression. Additionally, we investigated the effect of Adgrl3-depletion at the transcriptomic level by RNA-sequencing three ADHD-relevant brain regions: prefrontal cortex (PFC), hippocampus and striatum.Adgrl3(-/-) mice show increased locomotive activity across all tests and subtle gait abnormalities. These mice also show impairments across spatial memory and learning domains, alongside increased levels of impulsivity and sociability with decreased aggression. However, these alterations were absent in Adgrl3(-/-) mice. Across all brain regions tested, the numbers of genes found to exhibit differential expression was relatively small, indicating a specific pathway of action, rather than a broad neurobiological perturbation. Gene-set analysis of differential expression in the PFC detected a number of ADHD-relevant pathways including dopaminergic synapses as well as cocaine and amphetamine addiction. The Slc6a3 gene coding for the dopamine transporter was the most dysregulated gene in the PFC. Unexpectedly, several neurohormone/peptides which are typically only expressed in the hypothamalus were found to be dysregulated in the striatum. Our study further validates Adgrl3 constitutive knockout mice as an experimental model of ADHD while providing neuroanatomical targets for future studies involving ADGRL3 modified models.This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.

AB - Adhesion G protein-coupled receptor L3 (ADGRL3, LPHN3) has putative roles in neuronal migration and synapse function. Various polymorphisms in ADGRL3 have been linked with an increased risk of attention deficit/hyperactivity disorder (ADHD). In this study, we examined the characteristics of Adgrl3-deficient mice in multiple behavioural domains related to ADHD: locomotive activity, impulsivity, gait, visuospatial and recognition memory, sociability, anxiety-like behaviour and aggression. Additionally, we investigated the effect of Adgrl3-depletion at the transcriptomic level by RNA-sequencing three ADHD-relevant brain regions: prefrontal cortex (PFC), hippocampus and striatum.Adgrl3(-/-) mice show increased locomotive activity across all tests and subtle gait abnormalities. These mice also show impairments across spatial memory and learning domains, alongside increased levels of impulsivity and sociability with decreased aggression. However, these alterations were absent in Adgrl3(-/-) mice. Across all brain regions tested, the numbers of genes found to exhibit differential expression was relatively small, indicating a specific pathway of action, rather than a broad neurobiological perturbation. Gene-set analysis of differential expression in the PFC detected a number of ADHD-relevant pathways including dopaminergic synapses as well as cocaine and amphetamine addiction. The Slc6a3 gene coding for the dopamine transporter was the most dysregulated gene in the PFC. Unexpectedly, several neurohormone/peptides which are typically only expressed in the hypothamalus were found to be dysregulated in the striatum. Our study further validates Adgrl3 constitutive knockout mice as an experimental model of ADHD while providing neuroanatomical targets for future studies involving ADGRL3 modified models.This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.

KW - AMYGDALA MORPHOLOGY

KW - ANIMAL-MODEL

KW - ATTENTION-DEFICIT/HYPERACTIVITY DISORDER

KW - Adhesion G protein-coupled receptor L3 (ADGRL3)

KW - Attention-deficit/hyperactivity disorder (ADHD)

KW - CHILDREN

KW - GAIT

KW - GENOME-WIDE ASSOCIATION

KW - Hippocampus

KW - LPHN3

KW - Latrophilin

KW - Latrophilin 3 (LPHN3)

KW - METHYLPHENIDATE

KW - Mouse model

KW - NEUROTRANSMISSION

KW - PREFRONTAL CORTEX

KW - Prefrontal cortex

KW - Striatum

KW - SUSCEPTIBILITY

KW - HIPPOCAMPUS

U2 - 10.1016/j.neuropharm.2019.02.039

DO - 10.1016/j.neuropharm.2019.02.039

M3 - Article

C2 - 30849401

SN - 0028-3908

VL - 156

JO - Neuropharmacology

JF - Neuropharmacology

M1 - 107557

ER -