Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition

O Rivero, M M Selten, S Sich, S Popp, L Bacmeister, E Amendola, M Negwer, D Schubert, F Proft, D Kiser, A G Schmitt, C Gross, S M Kolk, T Strekalova, D van den Hove, T J Resink, N Nadif Kasri, K P Lesch

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Scopus)

Abstract

Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo)phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13(-/-) mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13(-/-) mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism.

Original languageEnglish
Article numbere655
JournalTranslational Psychiatry
Volume5
DOIs
Publication statusPublished - 13 Oct 2015

Keywords

  • Animals
  • Attention Deficit Disorder with Hyperactivity
  • Cadherins
  • Disease Models, Animal
  • Genes, Tumor Suppressor
  • Hippocampus
  • Interneurons
  • Learning
  • Memory
  • Mice
  • Psychopathology
  • Synaptic Transmission
  • gamma-Aminobutyric Acid

Cite this

Rivero, O ; Selten, M M ; Sich, S ; Popp, S ; Bacmeister, L ; Amendola, E ; Negwer, M ; Schubert, D ; Proft, F ; Kiser, D ; Schmitt, A G ; Gross, C ; Kolk, S M ; Strekalova, T ; van den Hove, D ; Resink, T J ; Nadif Kasri, N ; Lesch, K P. / Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition. In: Translational Psychiatry. 2015 ; Vol. 5.
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title = "Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition",
abstract = "Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo)phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13(-/-) mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13(-/-) mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism.",
keywords = "Animals, Attention Deficit Disorder with Hyperactivity, Cadherins, Disease Models, Animal, Genes, Tumor Suppressor, Hippocampus, Interneurons, Learning, Memory, Mice, Psychopathology, Synaptic Transmission, gamma-Aminobutyric Acid",
author = "O Rivero and Selten, {M M} and S Sich and S Popp and L Bacmeister and E Amendola and M Negwer and D Schubert and F Proft and D Kiser and Schmitt, {A G} and C Gross and Kolk, {S M} and T Strekalova and {van den Hove}, D and Resink, {T J} and {Nadif Kasri}, N and Lesch, {K P}",
year = "2015",
month = "10",
day = "13",
doi = "10.1038/tp.2015.152",
language = "English",
volume = "5",
journal = "Translational Psychiatry",
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Rivero, O, Selten, MM, Sich, S, Popp, S, Bacmeister, L, Amendola, E, Negwer, M, Schubert, D, Proft, F, Kiser, D, Schmitt, AG, Gross, C, Kolk, SM, Strekalova, T, van den Hove, D, Resink, TJ, Nadif Kasri, N & Lesch, KP 2015, 'Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition', Translational Psychiatry, vol. 5, e655. https://doi.org/10.1038/tp.2015.152

Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition. / Rivero, O; Selten, M M; Sich, S; Popp, S; Bacmeister, L; Amendola, E; Negwer, M; Schubert, D; Proft, F; Kiser, D; Schmitt, A G; Gross, C; Kolk, S M; Strekalova, T; van den Hove, D; Resink, T J; Nadif Kasri, N; Lesch, K P.

In: Translational Psychiatry, Vol. 5, e655, 13.10.2015.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition

AU - Rivero, O

AU - Selten, M M

AU - Sich, S

AU - Popp, S

AU - Bacmeister, L

AU - Amendola, E

AU - Negwer, M

AU - Schubert, D

AU - Proft, F

AU - Kiser, D

AU - Schmitt, A G

AU - Gross, C

AU - Kolk, S M

AU - Strekalova, T

AU - van den Hove, D

AU - Resink, T J

AU - Nadif Kasri, N

AU - Lesch, K P

PY - 2015/10/13

Y1 - 2015/10/13

N2 - Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo)phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13(-/-) mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13(-/-) mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism.

AB - Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo)phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13(-/-) mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13(-/-) mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism.

KW - Animals

KW - Attention Deficit Disorder with Hyperactivity

KW - Cadherins

KW - Disease Models, Animal

KW - Genes, Tumor Suppressor

KW - Hippocampus

KW - Interneurons

KW - Learning

KW - Memory

KW - Mice

KW - Psychopathology

KW - Synaptic Transmission

KW - gamma-Aminobutyric Acid

U2 - 10.1038/tp.2015.152

DO - 10.1038/tp.2015.152

M3 - Article

C2 - 26460479

VL - 5

JO - Translational Psychiatry

JF - Translational Psychiatry

SN - 2158-3188

M1 - e655

ER -