TY - JOUR
T1 - Early-life stress impairs developmental programming in Cadherin 13 (CDH13)-deficient mice
AU - Kiser, Dominik P.
AU - Popp, Sandy
AU - Schmitt-Boehrer, Angelika G.
AU - Strekalova, Tatyana
AU - van den Hove, Daniel L.
AU - Lesch, Klaus-Peter
AU - Rivero, Olga
N1 - Funding Information:
D.P.K. was supported by a grant of the German Excellence Initiative to the Graduate School of Life Sciences (GSLS) and the DFG Research Training Group, RTG 1253, University of Würzburg. O.R. was supported by the Jacobs Foundation. K.P.L. and T.S. are supported by the European Union's Seventh Framework Programme under Grant No. 602805 (Aggressotype), the Horizon 2020 Research and Innovation Programme under Grant No. 728018 (Eat2beNICE), the 5-100 Russian Academic Excellence Project). K.P.L., D.V.D.H. and O.R. are additionally supported by the DFG (SFB TRR 58/A5). K.P.L. and O.R. are also supported by the Fritz Thyssen Foundation (Az.10.13.1185). The funding sources had no role in concept design, selection of articles, the decision to publish or the preparation of the manuscript. We thank the Core Unit Systems Medicine (SysMed), University of Wuerzburg, Germany, and specifically Dr. K. Förstner and M. Göbel, for processing of our RNA samples and preparation of the raw data. The data presented is also part of the doctoral thesis from D.P.K. Furthermore we thank G. Ortega and S. Falger for their invaluable help in the laboratories and animal facilities. A special thank also goes to T. Gerstle and T. Ganster who helped during sample acquisition, M. Weider, R. Lardenoije and P. Ehsan who helped out with valuable insights into the analysis of the RNA dataset, as well as Dr. S. Roy Chowdhury and Dr. H. Faist for proof reading.
Funding Information:
D.P.K. was supported by a grant of the German Excellence Initiative to the Graduate School of Life Sciences (GSLS) and the DFG Research Training Group, RTG 1253, University of Würzburg . O.R. was supported by the Jacobs Foundation . K.P.L. and T.S. are supported by the European Union's Seventh Framework Programme under Grant No. 602805 (Aggressotype), the Horizon 2020 Research and Innovation Programme under Grant No. 728018 (Eat2beNICE), the 5-100 Russian Academic Excellence Project). K.P.L., D.V.D.H. and O.R. are additionally supported by the DFG ( SFB TRR 58/A5 ). K.P.L. and O.R. are also supported by the Fritz Thyssen Foundation ( Az.10.13.1185 ). The funding sources had no role in concept design, selection of articles, the decision to publish or the preparation of the manuscript. We thank the Core Unit Systems Medicine (SysMed), University of Wuerzburg, Germany, and specifically Dr. K. Förstner and M. Göbel, for processing of our RNA samples and preparation of the raw data. The data presented is also part of the doctoral thesis from D.P.K. Furthermore we thank G. Ortega and S. Falger for their invaluable help in the laboratories and animal facilities. A special thank also goes to T. Gerstle and T. Ganster who helped during sample acquisition, M. Weider, R. Lardenoije and P. Ehsan who helped out with valuable insights into the analysis of the RNA dataset, as well as Dr. S. Roy Chowdhury and Dr. H. Faist for proof reading.
Publisher Copyright:
© 2018 The Authors
PY - 2019/3/8
Y1 - 2019/3/8
N2 - Objective: Cadherin-13 (CDH13), a member of the calcium-dependent cell adhesion molecule family, has been linked to neurodevelopmental disorders, including autism spectrum (ASD) and attention-deficit/hyperactivity (ADHD) disorders, but also to depression. In the adult brain, CDH13 expression is restricted e.g. to the presynaptic compartment of inhibitory GABAergic synapses in the hippocampus and Cdh13 knockout mice show an increased inhibitory drive onto hippocampal CA1 pyramidal neurons, leading to a shift in excitatory/inhibitory balance. CDH13 is also moderating migration of serotonergic neurons in the dorsal raphe nucleus, establishing projections preferentially to the thalamus and cerebellum during brain development. Furthermore, CDH13 is upregulated by chronic stress as well as in depression, suggesting a role in early-life adaptation to stressful experience. Here, we therefore investigated the interaction between Cdh13 variation and neonatal maternal separation (MS) in mice.Methods: Male and female wild-type (Cdh13(+/+)), heterozygous (Cdh13(+/-)) and homozygous (Cdh13(-)(/-)) knockout mice exposed to MS, or daily handling as control, were subjected to a battery of behavioural tests to assess motor activity, learning and memory as well as anxiety-like behaviour. A transcriptome analysis of the hippocampus was performed in an independent cohort of mice which was exposed to MS or handling, but remained naive for behavioural testing.Results: MS lead to increased anxiety-like behaviour in Cdh13(-/-) mice compared to the other two MS groups. Cdh13(-/-) mice showed a context-dependent effect on stress- and anxiety-related behaviour, impaired extinction learning following contextual fear conditioning and decreased impulsivity, as well as a mild decrease in errors in the Barnes maze and reduced risk-taking in the light-dark transition test after MS. We also show sex differences, with increased locomotor activity in female Cdh13(-/-) mice, but unaltered impulsivity and activity in male Cdh13(-/-) mice. Transcriptome analysis revealed several pathways associated with cell surface/adhesion molecules to be altered following Cdh13 deficiency, together with an influence on endoplasmic reticulum function.Conclusion: MS resulted in increased stress resilience, increased exploration and an overall anxiolytic behavioural phenotype in male Cdh13(+/+) and Cdh13(+/-) mice. Cdh13 deficiency, however, obliterated most of the effects caused by early-life stress, with Cdh13(-/-) mice exhibiting delayed habituation, no reduction of anxiety-like behaviour and decreased fear extinction. Our behavioural findings indicate a role of CDH13 in the programming of and adaptation to early-life stress. Finally, our transcriptomic data support the view of CDH13 as a neuroprotective factor as well as a mediator in cell-cell interactions, with an impact on synaptic plasticity.
AB - Objective: Cadherin-13 (CDH13), a member of the calcium-dependent cell adhesion molecule family, has been linked to neurodevelopmental disorders, including autism spectrum (ASD) and attention-deficit/hyperactivity (ADHD) disorders, but also to depression. In the adult brain, CDH13 expression is restricted e.g. to the presynaptic compartment of inhibitory GABAergic synapses in the hippocampus and Cdh13 knockout mice show an increased inhibitory drive onto hippocampal CA1 pyramidal neurons, leading to a shift in excitatory/inhibitory balance. CDH13 is also moderating migration of serotonergic neurons in the dorsal raphe nucleus, establishing projections preferentially to the thalamus and cerebellum during brain development. Furthermore, CDH13 is upregulated by chronic stress as well as in depression, suggesting a role in early-life adaptation to stressful experience. Here, we therefore investigated the interaction between Cdh13 variation and neonatal maternal separation (MS) in mice.Methods: Male and female wild-type (Cdh13(+/+)), heterozygous (Cdh13(+/-)) and homozygous (Cdh13(-)(/-)) knockout mice exposed to MS, or daily handling as control, were subjected to a battery of behavioural tests to assess motor activity, learning and memory as well as anxiety-like behaviour. A transcriptome analysis of the hippocampus was performed in an independent cohort of mice which was exposed to MS or handling, but remained naive for behavioural testing.Results: MS lead to increased anxiety-like behaviour in Cdh13(-/-) mice compared to the other two MS groups. Cdh13(-/-) mice showed a context-dependent effect on stress- and anxiety-related behaviour, impaired extinction learning following contextual fear conditioning and decreased impulsivity, as well as a mild decrease in errors in the Barnes maze and reduced risk-taking in the light-dark transition test after MS. We also show sex differences, with increased locomotor activity in female Cdh13(-/-) mice, but unaltered impulsivity and activity in male Cdh13(-/-) mice. Transcriptome analysis revealed several pathways associated with cell surface/adhesion molecules to be altered following Cdh13 deficiency, together with an influence on endoplasmic reticulum function.Conclusion: MS resulted in increased stress resilience, increased exploration and an overall anxiolytic behavioural phenotype in male Cdh13(+/+) and Cdh13(+/-) mice. Cdh13 deficiency, however, obliterated most of the effects caused by early-life stress, with Cdh13(-/-) mice exhibiting delayed habituation, no reduction of anxiety-like behaviour and decreased fear extinction. Our behavioural findings indicate a role of CDH13 in the programming of and adaptation to early-life stress. Finally, our transcriptomic data support the view of CDH13 as a neuroprotective factor as well as a mediator in cell-cell interactions, with an impact on synaptic plasticity.
KW - Cadherin-13 (CDH13)
KW - T-cadherin
KW - Neurodevelopment
KW - Autism
KW - ADHD
KW - Depression
KW - Psychiatric disorders
KW - Early-life stress
KW - Mouse
KW - RNA sequencing
KW - Endoplasmic reticulum stress
KW - Adhesion
KW - AUTISM SPECTRUM DISORDER
KW - GENOME-WIDE ASSOCIATION
KW - ATTENTION-DEFICIT/HYPERACTIVITY DISORDER
KW - VASCULAR ENDOTHELIAL-CELLS
KW - UNFOLDED PROTEIN RESPONSE
KW - T-CADHERIN
KW - MATERNAL SEPARATION
KW - SYMPTOMS
KW - GENE
U2 - 10.1016/j.pnpbp.2018.08.010
DO - 10.1016/j.pnpbp.2018.08.010
M3 - Article
C2 - 30165120
SN - 0278-5846
VL - 89
SP - 158
EP - 168
JO - Progress in Neuro-Psychopharmacology & Biological Psychiatry
JF - Progress in Neuro-Psychopharmacology & Biological Psychiatry
ER -