One of the most important steps in postnatal brain development is the formation of the connections between neurons, known as synapses. These connections establish the neural circuits that control behavior. NMDA receptors are key molecules in the development and functioning of synapses that use the neurotransmitter glutamate.

Mutations in NMDA receptor subunits have been associated with autism, as well as with epilepsy and intellectual disability — two disorders that are highly comorbid with autism.

Shasta Sabo and her colleagues at Case Western Reserve University in Cleveland, Ohio, set out to determine whether and how autism-linked mutations in NMDA receptors contribute to autism. Because of its important role in brain development, they specifically focused on the NR2B/GRIN2B subunit of the NMDA receptor. First, they generated NR2B subunits bearing mutations identified in individuals with autism. Then they conducted a series of experiments to determine whether these mutant subunits alter NMDA receptor function and delivery to synapses.

They found that each NR2B mutation affects NMDA receptor function, but at varying magnitudes of functional impairment. Each mutation alters NMDA receptor function through distinct mechanisms: One alters NMDA receptor function without altering its localization, a second impairs trafficking of the receptors to the cell surface and a third mutation lowers overall expression of the receptor.

The team’s results provide the first demonstration that autism-associated mutations in NMDA receptor subunits affect the function of the receptor, supporting the hypothesis that the mutations may be pathogenic. These observations also lay the groundwork for producing autism mouse models with mutations in NMDA receptors, which would allow researchers to determine their effects on synapse development and behavior in vivo.