Autism associated mutation in Cacna1d causes perseverative behavioral phenotype in mice

Area of Science:

• Neuroscience
• Genetics
• Behavioral Science

Background:

• Behavioral inflexibility and perseveration are key features of autism spectrum disorder (ASD).
• Mutations in CACNA1D, encoding the Cav1.3 L-type calcium channel, are associated with ASD, but their specific behavioral effects are not fully understood.

Purpose of the Study:

• To investigate the behavioral consequences of an autism-associated gain-of-function mutation in Cacna1d.
• To assess the role of Cav1.3 calcium channels in behavioral flexibility and perseverative behaviors relevant to ASD.

Main Methods:

• Examined mice with the Cacna1d G407R gain-of-function mutation using a battery of behavioral assays.
• Assessed spatial learning, reversal learning, instrumental conditioning, repetitive behaviors (grooming, marble burying, nestlet shredding), anxiety, and locomotion.

Main Results:

• Mutant mice displayed normal learning rates for initial discriminations and contingencies.
• Deficits in reversal learning were observed under conditions of overtraining and probabilistic reinforcement.
• Mutant mice exhibited increased grooming, marble burying, and nestlet shredding, indicating enhanced perseverative behavior.
• Anxiety and general locomotion remained unaffected in mutant mice.

Conclusions:

• Gain-of-function mutations in Cav1.3 selectively impair behavioral flexibility.
• These findings support a role for calcium-dependent corticostriatal plasticity in autism-associated perseveration.