Neuroligin 1 Regulates Autistic-Like Repetitive Behavior through Modulating the Activity of Striatal D2...

Area of Science:

• Neuroscience
• Genetics
• Cellular Biology

Background:

• Restricted and repetitive behaviors (RRBs) are core symptoms of autism spectrum disorder (ASD).
• The underlying cellular and neural mechanisms of RRBs are not well understood.
• The ASD-related protein Neuroligin 1 (NLGN1) plays a role in neuronal function.

Purpose of the Study:

• To investigate the role of NLGN1 in D2-MSNs of the dorsal striatum in the generation of RRBs.
• To identify the cellular and molecular mechanisms linking NLGN1 deficiency to excessive repetitive behaviors.
• To explore potential therapeutic targets for ASD-related RRBs.

Main Methods:

• Utilized mouse models with NLGN1 deficiency in D2-MSNs.
• Measured the duration and frequency of self-grooming and digging behaviors.
• Employed neuronal activity inhibition techniques.
• Conducted single-nucleus RNA sequencing (sn-RNAseq) and protein detection.
• Assessed protein kinase C (PKC) activity.

Main Results:

• Absence of NLGN1 in D2-MSNs correlated with increased duration and frequency of self-grooming and digging.
• NLGN1-deficient D2-MSNs showed hyperactivation, linked to excessive RRBs.
• Inhibiting D2-MSN activity reduced RRB occurrence.
• Distinct D2-MSN activity patterns underlie self-grooming and digging.
• Overactivation of PKC in NLGN1-deficient mice contributed to RRBs and neuronal hyperexcitability.

Conclusions:

• NLGN1 deficiency in D2-MSNs is a key factor in generating specific RRBs in ASD.
• PKC overactivation is a potential molecular mechanism driving these behaviors.
• Targeting D2-MSN activity and PKC signaling may offer novel therapeutic strategies for ASD.