Balance between two competing nerve proteins deters symptoms of autism in mice

In mice, autism symptoms arise when a certain pair of competing nerve proteins falls out of equilibrium, according to a study published April 1^st in the open-access journal PLOS Biology by Dongdong Zhao of Wenzhou Medical University, China, Yun-wu Zhang of Xiamen University, China, and colleagues.

Approximately 1% of the world population is considered to have Autism Spectrum Disorder (ASD), exhibiting a series of social and cognitive symptoms. Previous research has linked certain genetic factors to ASD, including many associated with neuron activity, but it remains unclear exactly how these factors are related. In this study, Zhao, Zhang and colleagues used mice to examine the activity of two neuronal proteins suspected to be linked to ASD.

MDGA2 is a protein involved in the transmission of nerve signals, and certain mutations in the MDGA2 gene have been identified in ASD patients. Experimental trials revealed that mice with reduced levels of MDGA2 exhibited ASD-like symptoms, including repetitive grooming and altered social behavior. These mice also exhibited increased activity in certain nerve synapses and increased levels of BDNF, another neuronal protein that has been linked to ASD and functions through binding and activating the TrkB protein. When these mice were treated with an artificial peptide that mimicked MDGA2 and inhibited BDNF/TrkB activity, the symptoms lessened.

Based on these results combined with previous research, the authors suggest that MDGA2 and BDNF maintain a natural balance by competing with each other for TrkB protein binding sites, and disruption to this system can lead to regulatory changes in neuron activity related to ASD. This protein system might be a promising target for future therapeutic treatments, but further investigation will be required into the exact functions of this system and its relationship to ASD symptoms.

Yun-wu Zhang adds, “Mutations in the MDGA2 gene causes autism spectrum disorders (ASD) but the underlying mechanism is elusive. Our study reveals a novel role of MDGA2 in keeping the BDNF/TrkB signaling at bay for normal excitatory neuronal activity, and demonstrates that MDGA2 deficiency results in aberrant BDNF/TrkB activation and elevated excitatory neuronal activity, leading to ASD-like phenotypes in mice.”

In your coverage, please use this URL to provide access to the freely available paper in PLOS Biology: https://plos.io/4hJ3amN  

Citation: Zhao D, Huo Y, Zheng N, Zhu X, Yang D, Zhou Y, et al. (2025) Mdga2 deficiency leads to an aberrant activation of BDNF/TrkB signaling that underlies autism-relevant synaptic and behavioral changes in mice. PLoS Biol 23(3): e3003047. https://doi.org/10.1371/journal.pbio.3003047

Author countries: China

Funding: This work was supported by grants from the National Natural Science Foundation of China (82001442 to D.Z., and 82130039 and U21A20361 to Y.-w.Z.), and Postdoctoral Science Foundation of China (2020M671948 to D.Z., and 2022M722651 to Y.H.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.