Numb deficiency causes impaired trafficking of mGlu5 in neurons and autistic-like behaviors.

Protein Numb localizes to clathrin-coated vesicles and participates in the trafficking of trans-membrane receptors. We previously reported that Numb deficiency in cerebellar Purkinje cells impairs synaptic expression of metabotropic glutamate receptor 1 (mGlu1) and motor coordination. However, the functions of Numb in other brain regions have not been investigated. Here, we show that Numb regulates the membrane expression of metabotropic glutamate receptor 5 (mGlu5) and is critical to social behaviors. Numb binds to mGlu5 and promotes the membrane expression of mGlu5 by antagonizing its internalization and recycling. Interestingly, the conditional knockout of Numb and its homologous gene, Numblike, in excitatory neurons leads to a significant deficit in the three-chamber social test. Together, our work suggests that Numb is required for social interaction by modulating the functions of mGlu5.

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