A rare autism-associated MINT2/APBA2 mutation disrupts neurexin trafficking and synaptic function

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• MINT2/APBA2 is a synaptic adaptor protein crucial for excitatory synaptic transmission.
• Nonsynonymous coding variants in MINT2 are linked to autism spectrum disorders (ASDs), but their functional impact and pathogenic mechanisms remain unclear.
• Neurexin-1α (Nrxn1α) is a presynaptic cell-adhesion protein implicated in ASDs.

Purpose of the Study:

• To investigate the synaptic effects of the rat Mint2 N723S mutation, equivalent to the human MINT2 N722S mutation associated with ASDs.
• To elucidate the pathogenic mechanisms by examining the mutation's impact on Nrxn1α interaction, stabilization, and trafficking.

Main Methods:

• Utilized time-lapse imaging in primary mouse neurons to observe the behavior of wild-type and mutant Mint2.
• Assessed Nrxn1α stabilization, membrane trafficking, and localization at presynaptic terminals.
• Quantified Nrxn-mediated synaptogenesis and miniature event frequency in excitatory synapses.

Main Results:

• The Mint2 N723S mutation impairs Nrxn1α stabilization and surface trafficking without affecting Nrxn1α binding.
• Mutant Mint2 exhibited increased immobile puncta on neuronal processes, suggesting altered co-transport.
• The mutation led to aberrant Nrxn1α localization at presynaptic terminals, decreased Nrxn-mediated synaptogenesis, and reduced miniature event frequency.

Conclusions:

• The Mint2 N723S mutation causes neuronal dysfunction relevant to ASDs.
• Alterations in Nrxn1α surface trafficking and synaptic function are key mechanisms underlying Mint2-associated neurodevelopmental deficits.