A Celsr3 Mutation Linked to Tourette Disorder Disrupts Cortical Dendritic Patterning and Striatal Cholinergic...

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Tourette Disorder (TD) is a neurodevelopmental condition with poorly understood genetic and brain mechanisms.
• The gene CELSR3 is a high-confidence risk gene associated with TD.

Purpose of the Study:

• To investigate the molecular underpinnings of TD by creating a novel mouse model with a human CELSR3 mutation.
• To analyze the effects of the Celsr3^R774H mutation on neuronal development, function, and behavior.

Main Methods:

• Generated a mouse model expressing the human CELSR3 R774H variant.
• Utilized 3D geometric analysis for dendritic patterning and spine analysis.
• Performed patch clamp recordings in striatal cholinergic interneurons.
• Assessed behavioral phenotypes including motor activity and sensorimotor gating.

Main Results:

• Homozygous Celsr3^R774H mice are viable with normal gross forebrain development.
• Alterations in dendritic patterning and spine characteristics were observed in cortical pyramidal neurons.
• Mild intrinsic hyperexcitability and altered spine density were found in striatal cholinergic interneurons.
• Celsr3^R774H homozygous males exhibited sensorimotor gating deficits, a TD-relevant phenotype.

Conclusions:

• Human CELSR3 mutations may disrupt dendritic patterning, spine dynamics, and neuronal firing in cortico-striatal circuits.
• The Celsr3^R774H mouse model recapitulates specific behavioral deficits relevant to Tourette Disorder.
• This study provides insights into the neurobiological mechanisms linking CELSR3 variants to TD pathophysiology.