Proteins Regulating NMDA Receptor Function Offer New Hope for Autism Treatments

A research team has uncovered a detailed molecular mechanism that controls the activity of the NMDA (N-methyl-D-aspartate) glutamate receptor, a crucial component involved in excitatory synaptic transmission in the brain. This breakthrough could lead to the development of innovative, targeted therapies for neurological conditions such as autism spectrum disorder (ASD). The study, published in Progress in Neurobiology, was led by Professors Ko Jaewon and Um Ji Won from DGIST’s Center for Synapse Diversity and Specificity.

Synapses, the communication points between neurons, rely heavily on electrical signals, with NMDA receptors playing a vital role in shaping the intensity and duration of these signals. Dysregulation of NMDA receptor activity, whether excessive or diminished, can disrupt normal brain function, potentially contributing to neurodevelopmental disorders.

The team has identified 'switch proteins,' which directly inhibit NMDA receptor activity. Central to this discovery is the interaction between MDGA2, a MAM domain-containing glycosylphosphatidylinositol (GPI) anchor protein, and EphB2, a receptor tyrosine kinase that typically activates NMDA receptors. The researchers demonstrated that MDGA2 competitively binds to EphB2, preventing its activation of NMDA receptors, thereby serving as a molecular regulator.

Utilizing advanced AI-based protein structure prediction tools such as ColabFold, the scientists mapped the specific binding sites of MDGA2 and EphB2, highlighting targeted amino acid residues critical for their interaction. Cellular experiments confirmed that this interaction effectively inhibits NMDA receptor activation.

Since 2011, DGIST’s CSDS has been dedicated to exploring protein pathways that regulate synapse formation and function. Earlier studies suggested MDGA proteins inhibit synapse development, and recent research confirmed that knocking out MDGA1 and MDGA2 reduces synaptic density and neurotransmission efficiency. The latest findings elaborate on this by illustrating how MDGA2 specifically binds to EphB2 to inhibit NMDA receptors, thereby influencing excitatory synaptic transmission.

This insight provides a promising foundation for precise modulation of neural circuits. It also opens avenues for designing drugs that can normalize overactive synapses, which are often observed in autism, potentially reducing symptoms and side effects of existing treatments. Professor Um emphasized that MDGA2 functions as a conductor, coordinating excitatory synapse activity by disrupting key adhesion proteins, offering new strategies for intervention.

Looking ahead, researchers intend to extend their studies into preclinical models, emphasizing the relevance of EphB2 and MDGA2 in brain developmental disorders like autism spectrum disorder. These advancements could lead to the development of targeted therapies that regulate specific neural pathways, offering hope for improved management of neurodevelopmental conditions.