CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice

D. Halperin, A. Stavsky, R. Kadir, M. Drabkin, O. Wormser, Y. Yogev, V. Dolgin, R. Proskorovski-Ohayon, Y. Perez, H. Nudelman, O. Stoler, B. Rotblat, T. Lifschytz, A. Lotan, G. Meiri, D. Gitler, O. S. Birk

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric disorder characterized by inattention, impulsivity and hyperactivity. ADHD exhibits substantial heritability, with rare monogenic variants contributing to its pathogenesis. Here we demonstrate familial ADHD caused by a missense mutation in CDH2, which encodes the adhesion protein N-cadherin, known to play a significant role in synaptogenesis; the mutation affects maturation of the protein. In line with the human phenotype, CRISPR/Cas9-mutated knock-in mice harboring the human mutation in the mouse ortholog recapitulated core behavioral features of hyperactivity. Symptoms were modified by methylphenidate, the most commonly prescribed therapeutic for ADHD. The mutated mice exhibited impaired presynaptic vesicle clustering, attenuated evoked transmitter release and decreased spontaneous release. Specific downstream molecular pathways were affected in both the ventral midbrain and prefrontal cortex, with reduced tyrosine hydroxylase expression and dopamine levels. We thus delineate roles for CDH2-related pathways in the pathophysiology of ADHD.

Original languageEnglish
Article number6187
JournalNature Communications
Volume12
Issue number1
DOIs
StatePublished - 1 Dec 2021

ASJC Scopus subject areas

  • Chemistry (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • Physics and Astronomy (all)

Fingerprint

Dive into the research topics of 'CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice'. Together they form a unique fingerprint.

Cite this