Sh3rf3 Deficiency drives autism-like behaviors via presynaptic dysfunction in mice

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a significant genetic component.
• The specific role of the candidate gene SH3RF3 in ASD pathophysiology is not well understood.

Purpose of the Study:

• To elucidate the biological function of SH3RF3 in neuronal synapses.
• To investigate the molecular mechanisms underlying SH3RF3's role in ASD.

Main Methods:

• Investigated SH3RF3's function as a scaffold protein in presynaptic vesicle docking.
• Analyzed the interaction between SH3RF3, BRSK1/SAD-B kinase, and RIM1 protein.
• Utilized genetic ablation of Sh3rf3 in mice to study synaptic and behavioral consequences.
• Performed prefrontal cortex-specific restoration of Sh3rf3 in knockout mice.
• Characterized the SH3RF3 interactome to identify associated molecular networks.

Main Results:

• SH3RF3 facilitates presynaptic vesicle docking by forming a complex with BRSK1/SAD-B and RIM1.
• Genetic deletion of Sh3rf3 disrupts this complex, reduces RIM1 phosphorylation, and impairs synaptic vesicle dynamics.
• Synaptic transmission deficits, altered excitatory-inhibitory balance, and autistic-like behaviors were observed in Sh3rf3 knockout mice.
• Restoring Sh3rf3 in the prefrontal cortex ameliorated these functional and behavioral deficits.
• The SH3RF3 interactome revealed a network of ASD-risk genes, suggesting shared pathways.

Conclusions:

• SH3RF3 is an essential synaptic scaffold protein involved in regulating presynaptic function and excitatory transmission.
• Dysregulation of SH3RF3 contributes to synaptic dysfunction and autistic-like behaviors, highlighting its role in ASD.
• Targeting synaptic pathways involving SH3RF3 may offer therapeutic potential for ASD.