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

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

doi:10.1038/tp.2015.152

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.

Highlights

Brain development and plasticity are complex processes that require precise and specific interneuronal contacts to ensure the correct establishment of circuits at the cellular and systems level
A higher degree of colocalization is observed in the dorsal part of the hippocampus. n = 3; 100% = CDH13+ cells; percentages calculated from median. (e) Triple IF: CDH13 is colocalized with PV and SOM in some but not in all cells of the stratum oriens (SO)
Expression was detected in the SO of the cornu ammonis (CA) region, whereas weaker labeling was observed in scattered cells of the CA3 pyramidal layer, as well as the hilus and the granule cell layer of the dentate gyrus

Summary

Introduction

Brain development and plasticity are complex processes that require precise and specific interneuronal contacts to ensure the correct establishment of circuits at the cellular and systems level. To guarantee cellular and regional specification of synaptic contacts, the formation of neuronal networks is tightly controlled by a myriad of cell guidance and adhesion molecules, among which the cadherin superfamily of calcium-dependent cell adhesion molecules is of particular relevance.[1] after development, cadherins regulate the function and plasticity of mature synapses by participating in synaptic vesicle dynamics or controlling the stability of synaptic receptors.[1]. Cadherin-13 (CDH13, known as T-cadherin or H-cadherin) is an atypical member of the cadherin superfamily It lacks both transmembrane and cytoplasmic domains and is linked to the plasma membrane via a glycosylphosphatidylinositol moiety.[2,3,4] Genome-wide genetic approaches including linkage analyses, association studies and copy number variation studies have detected associations between the CDH13 gene and various neurodevelopmental disorders. CDH13 is expressed in the developing and adult brain, as well as in the cardiovascular system, where it exerts its function via lowadhesive homophilic or heterophilic interactions to control cell migration, neurite outgrowth and axon guidance.[24,25,26,27,28,29] We predicted that CDH13, as several other cell adhesion molecules, may have dual roles in the brain; as a guidance cue for migrating neurons and/or developing axons, and as a modulator of the establishment of specific synaptic contacts

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