Summary: Scientists have discovered that an imbalance between the neural proteins MDGA2 and BDNF can alter brain signaling in mice, leading to behaviors that resemble those seen in autism spectrum disorder. MDGA2 normally controls BDNF/TrkB signaling, but decreased levels of MDGA2 lead to increased neural activity and social impairment.
Mice with low levels of MDGA2 displayed autism-like behaviors, such as repeated worrying and withdrawal. Administering a peptide that imitates MDGA2 successfully rebalanced the protein levels and eased autism-like symptoms in mice, pointing to a promising avenue for future autism therapies.
Important facts:
- Neural protein disruption: Low levels of MDGA2 upset the balance of BDNF/TrkB signaling in the brain, disrupting normal neural communication and triggering autism spectrum disorder (ASD)-like symptoms.
- Behavioral changes: Affected mice repeatedly displayed behavioral and social deficits.
- Treatment potential: By mimicking MDGA2, symptoms were reduced and new treatment options emerged.
Source: PLOS
Published on April 1 in PLOS Biology, new research shows that disturbing the equilibrium between two key neural proteins can lead to autism-like behaviors in mice. The research, led by Dongdong Zhao of Wenzhou Medical University and Yunwu Zhang of Xiamen University in China, highlights how this protein imbalance may alter brain signaling in ways linked to autism spectrum disorder.
It is estimated that approximately 1% of the global population suffers from autism spectrum disorder (ASD), which manifests as a range of social and cognitive symptoms. Previous research has linked some genetic factors to ASD, many of which are related to neural activity, but the exact relationship between these factors is still unclear.
In this study, Zhao, Zhang and their colleagues used mice to investigate the activity of two neuronal proteins suspected of being linked to ASD. MDGA2 is a protein involved in nerve signaling. Some mutations in the MDGA2 gene have been identified in patients with ASD. Experimental studies have shown that mice with low levels of MDGA2 show ASD-like symptoms, such as frequent licking and impaired social behavior.
The mice in the study showed heightened activity at specific nerve synapses, along with elevated levels of BDNF—a neuronal protein linked to autism spectrum disorder (ASD) that binds to and activates the TrkB receptor. This overactivation of BDNF/TrkB signaling is believed to disrupt normal brain communication, contributing to the development of autism-like behaviors.
When treated with a synthetic peptide designed to mimic MDGA2 and block excessive BDNF/TrkB activity, the mice experienced a restoration of protein balance. This intervention not only normalized neural signaling but also reduced their ASD-like symptoms, pointing to a promising potential pathway for future autism therapies.
Based on these findings, combined with previous research, the authors propose that MDGA2 and BDNF maintain a natural balance by competing for TrkB protein binding sites. Disruption of this system may lead to regulatory changes in neuronal activity associated with ASD.
This protein system could represent a promising target for future therapeutic approaches to autism spectrum disorder (ASD). However, researchers emphasize that more work is needed to fully understand its precise functions and how disruptions in this system contribute to the development of ASD symptoms.
As study co-author Yun-wu Zhang explains, “Mutations in the MDGA2 gene cause autism spectrum disorder (ASD), but the underlying mechanism is still unclear.” This highlights the importance of continued investigation into the MDGA2–BDNF/TrkB pathway and its role in regulating brain function.
The researchers reported that their work uncovers a previously unknown role for MDGA2 in regulating BDNF/TrkB signaling, which is essential for maintaining normal excitatory neuronal activity. They found that when MDGA2 levels are deficient, BDNF/TrkB signaling becomes abnormally overactive, increasing excitatory neuronal activity and ultimately producing autism spectrum disorder (ASD)-like behaviors in mice.
Funding: This work was supported by grants from the National Natural Science Foundation of China (82001442 to DZ, 82130039 and U21A20361 to Y.-wZ) and the China Postdoctoral Science Foundation (2020M671948 to DZ and 2022M725 to Y.2.2022). The authors noted that the funding sources had no role in the study’s design, data collection or analysis, the decision to publish, or the preparation of the manuscript.
Abstract
MDGA2This deficiency leads to abnormal activity of BDNF/TrkB signaling, which underlies autism-related synaptic and behavioral changes in mice.
Memprin/A5/mu (MAM) domain-containing glycosylphosphatidylinositol anchor 2 (MDGA2) is an excitatory synaptic suppressor and mutations in it are associated with autism spectrum disorder (ASD). However, the detailed physiological function of MDGA2 and the mechanisms underlying ASD caused by MDGA2 deficiency remain to be elucidated. In this work, we not only confirmed that Mdga2 +/− mice exhibit impaired excitatory synaptic transmission and ASD-like behavior, but we also observed dysfunctional activity of brain-derived neurotrophic factor/tyrosine kinase B (BDNF/TrkB) signaling in these mice.
We show that MDGA2 interacts with TrkB through its memprin/A5/mu domain, thereby antagonizing BDNF binding to TrkB. Loss of MDGA2 and the ASD-associated V930I mutation of MDGA2 promote BDNF/TrkB signaling. The researchers demonstrated that blocking BDNF/TrkB signaling either with a small-molecule compound or an MDGA2-derived peptide could counteract the abnormal effects seen in MDGA2-deficient mice. These mice typically showed changes in social behavior driven by altered AMPA receptor activity, including both reduced and excessive social interactions.
By inhibiting this overactive signaling pathway, the treatments helped restore more balanced social activity. This finding not only sheds light on the molecular mechanisms linking MDGA2 deficiency to behavioral changes but also points to a potential therapeutic strategy for addressing autism-like symptoms.
These findings reveal a previously unknown MDGA2–BDNF/TrkB dependent pathway that plays a key role in regulating synaptic function. By uncovering this mechanism, the study points to a promising new avenue for developing targeted therapies for autism spectrum disorder (ASD).
