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

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Attention-deficit hyperactivity disorder (ADHD) is a prevalent childhood psychiatric disorder with significant heritability.
• Previous research suggests rare monogenic variants contribute to ADHD pathogenesis.

Purpose of the Study:

• To investigate the genetic basis of familial ADHD.
• To elucidate the role of the CDH2 gene and its encoded protein, N-cadherin, in ADHD pathophysiology.

Main Methods:

• Identified a missense mutation in CDH2 in familial ADHD cases.
• Utilized CRISPR/Cas9 technology to create knock-in mice modeling the human mutation.
• Assessed behavioral phenotypes, synaptic function, and molecular pathways in mutated mice.

Main Results:

• The CDH2 mutation impaired N-cadherin maturation and affected synaptogenesis.
• Mutated mice exhibited ADHD-like hyperactivity, responsive to methylphenidate.
• Synaptic dysfunction included impaired vesicle clustering and altered neurotransmitter release, with reduced dopamine levels in key brain regions.

Conclusions:

• A specific CDH2 mutation is implicated in familial ADHD.
• CDH2-related pathways and N-cadherin function are critical in ADHD pathophysiology.
• Findings highlight novel molecular targets for understanding and potentially treating ADHD.