Scientists at Wenzhou Medical University and Xiamen University have shown how autism symptoms in mice arise when a certain pair of competing nerve proteins falls out of equilibrium. The results of the team’s study, reported in PLOS Biology could point to potential therapeutic approaches for autism spectrum disorder (ASD). In their paper, titled “Mdfa2 deficiency leads to an aberrant activation of BDNF/TrkB signaling that underlies autism-relevant synaptic and behavioral changes in mice,” research leads Dongdong Zhao, PhD, at Wenzhou Medical University, and Yun-wu Zhang, PhD, at Xiamen University, and colleagues concluded that their findings “highlight a novel MDGA2- BDNF/TrkB-dependent mechanism underlying the synaptic function regulation, which may become a therapeutic target for ASD.”
Autism spectrum disorder is a complex neurodevelopmental disorder with its onset in early childhood, the authors noted. The disorder is characterized by reduced social interaction, increased stereotypic repetitive behavior, and altered cognition. “The prevalence of ASD has increased significantly in recent years, with approximately 1% of the world population considered to have the disorder,” the team noted. “Despite growing efforts devoted to this field, the etiology of ASD has yet to be fully elucidated.”
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. “So far, identified genes only explain a portion of ASD occurrence,” the investigators continued. “Identifying additional ASD-associated genes and revealing the underlying mechanisms should provide new insights into the pathogenesis of ASD and its treatment strategies.”
For their newly reported study Zhao, Zhang, and colleagues examined in mice the activity of two neuronal proteins suspected to be linked to ASD. One of these proteins, MDGA2, is involved in the transmission of nerve signals. “Memprin/A5/mu (MAM) domain-containing glycosylphosphatidylinositol anchor 2 (MDGA2) is an excitatory synaptic suppressor and its mutations have been associated with autism spectrum disorder (ASD),” the investigators further explained.
Their study revealed that mice with reduced levels of MDGA2 exhibited ASD-like symptoms, including repetitive grooming and altered social behavior. “… we found that Mdga2-deficient mice exhibited ASD-like behaviors including social deficits, repetitive behavior, and cognitive impairment,” the scientists noted. 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. “Growing evidence indicates that dysregulation of brain-derived neurotrophic factor (BDNF), including its abnormal protein levels and single nucleotide variations, is involved in ASD,” they further commented.
A scheme showing the mechanism underlying MDGA2-mediated944 BDNF/TrkB signaling pathway. [Dongdong Zhao, from Zhao D et al., 2025, PLOS Biology, CC-BY 4.0 (https://creativecommons.org/licenses/by/4.0/)]
A scheme showing the mechanism underlying the MDGA2-mediated BDNF/TrkB signaling pathway. [Dongdong Zhao, from Zhao D et al., 2025, PLOS Biology, CC-BY 4.0 (https://creativecommons.org/licenses/by/4.0/)\]
When these mice were treated using an artificial peptide that mimicked MDGA2 and inhibited BDNF/TrkB activity, the symptoms lessened. “Importantly, we demonstrate that inhibiting the BDNF/TrkB signaling by both small molecular compound and MDGA2-derived peptide can attenuate the increase of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated excitatory synaptic activity and social deficits in MDGA2-deficient mice,” they stated.
Based on these results, combined with those of 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, although further investigation will be required into the exact functions of this system and its relationship to ASD symptoms. “These findings collectively suggest that blockage of the interaction between BDNF and TrkB has therapeutic potential for ASD caused by MDGA2 deficiency,” the scientists concluded.
Yun-wu Zhang added, “Mutations in the MDGA2 gene cause 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 their paper, the team further stated, “Our work identifies a new mechanism underlying ASD pathogenesis caused by MDGA2 mutations and raises an urgent need to evaluate the exact function of the BDNF/TrkB signaling in ASD patients caused by different genetic and environment factors for designing precision treatment.”