Cntnap2 loss drives striatal neuron hyperexcitability and behavioral inflexibility

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Autism spectrum disorder (ASD) is characterized by social deficits and restricted, repetitive behaviors (RRBs).
• Striatal circuits are implicated in motor learning and habit formation, and their alterations may underlie RRBs in ASD.
• CNTNAP2 is a known risk gene for syndromic ASD, and its loss in mice is linked to RRBs.

Purpose of the Study:

• To investigate how the loss of CNTNAP2 impacts striatal neuron function.
• To determine if altered striatal neuron activity contributes to ASD-relevant motor behaviors in a mouse model.

Main Methods:

• Utilized Cntnap2 knockout (Cntnap2-/-) mice to study the effects of CNTNAP2 loss.
• Examined cortical input to direct pathway striatal projection neurons (dSPNs).
• Assessed intrinsic excitability of dSPNs and behavioral phenotypes.

Main Results:

• Cntnap2-/- mice showed enhanced cortical drive of dSPNs.
• This was attributed to increased intrinsic excitability of dSPNs, making them more responsive to cortical inputs.
• Cntnap2-/- mice exhibited spontaneous repetitive behaviors, enhanced motor routine learning, perseveration, and cognitive inflexibility.

Conclusions:

• Increased corticostriatal drive in dSPNs may contribute to the development of repetitive and inflexible behaviors observed in Cntnap2-/- mice.
• These findings highlight a potential mechanism linking CNTNAP2 dysfunction to ASD-related motor abnormalities.