Summary: A new study finds that autism-like behaviors appear in mice when two competing neuronal proteins—MDGA2 and BDNF—lose their balance. Under normal conditions, MDGA2 restrains BDNF/TrkB signaling; when MDGA2 levels fall, BDNF/TrkB activity rises, driving increased excitatory neuronal activity and social deficits.
Mice with reduced MDGA2 displayed behaviors resembling core features of autism spectrum disorder (ASD), including repetitive grooming and social withdrawal. Treating these mice with a peptide that mimics MDGA2 restored signaling balance and alleviated behavioral and synaptic abnormalities, pointing to a potential therapeutic target for ASD.
Key Facts:
- Protein imbalance: Loss of MDGA2 disrupts regulation of BDNF/TrkB signaling, producing ASD-like effects in mice.
- Behavioral impact: MDGA2-deficient mice exhibit repetitive behaviors and impaired social interaction.
- Therapeutic potential: An MDGA2-mimicking peptide and other inhibitors of BDNF/TrkB signaling reduced synaptic hyperactivity and improved social behaviors.
Source: PLOS
Overview
Researchers led by Dongdong Zhao (Wenzhou Medical University) and Yun-wu Zhang (Xiamen University) report in PLOS Biology that a delicate competition between MDGA2 and brain-derived neurotrophic factor (BDNF) for the TrkB receptor controls excitatory synaptic activity. Disruption of this balance produces synaptic and behavioral changes relevant to autism.
About 1% of people worldwide are estimated to be on the autism spectrum, a group of neurodevelopmental conditions marked by challenges in social communication and repetitive behaviors. Genetic studies have identified many genes linked to ASD, particularly those that influence neuronal connectivity and activity, but precise mechanisms remain unclear. This study focuses on the functional relationship between MDGA2 and BDNF/TrkB signaling in the brain and its relevance for autism-like traits in mice.
MDGA2 is a membrane-anchored protein that normally suppresses excitatory synaptic transmission. Mutations in MDGA2 have been found in individuals with ASD. In the study, heterozygous Mdga2+/− mice—mice with reduced MDGA2 expression—showed increased excitatory synaptic transmission, elevated BDNF levels, and behavioral changes including repetitive grooming and reduced social engagement.
Mechanistically, the authors show that MDGA2 interacts directly with the TrkB receptor via its memprin/A5/mu (MAM) domain and competes with BDNF for TrkB binding. Loss of MDGA2, or expression of an ASD-associated MDGA2 V930I variant, enhances BDNF/TrkB signaling and increases AMPA receptor–mediated excitatory activity at synapses.
Importantly, the team tested interventions that limit BDNF/TrkB signaling. Pharmacological inhibition and an MDGA2-derived peptide that blocks BDNF/TrkB overactivation both reduced AMPA receptor–dependent synaptic hyperactivity and ameliorated social deficits in MDGA2-deficient mice. These results suggest that restoring the MDGA2–BDNF/TrkB equilibrium can reverse key synaptic and behavioral abnormalities.
While these findings were obtained in mice and further research is needed to determine relevance in humans, the MDGA2–BDNF/TrkB axis emerges as a biologically plausible mechanism linking genetic variation to altered neuronal excitability and ASD-like behaviors. Targeting this pathway could inform the development of new treatments aimed at normalizing synaptic function in certain forms of ASD.
Yun-wu Zhang summarizes, “Mutations in the MDGA2 gene are associated with autism spectrum disorders, but underlying mechanisms were unclear. Our study reveals MDGA2’s role in restraining BDNF/TrkB signaling to maintain normal excitatory neuronal activity. MDGA2 deficiency produces aberrant BDNF/TrkB activation and elevated excitatory transmission, which underlie autism-relevant behaviors in mice.”
Funding: This work was funded by grants from the National Natural Science Foundation of China (82001442 to D.Z.; 82130039 and U21A20361 to Y.-w.Z.) and the Postdoctoral Science Foundation of China (2020M671948 to D.Z.; 2022M722651 to Y.H.). The funders did not influence study design, data collection and analysis, publication decisions, or manuscript preparation.
About this genetics and autism research news
Author: Claire Turner
Source: PLOS
Contact: Claire Turner – PLOS
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Mdga2 deficiency leads to an aberrant activation of BDNF/TrkB signaling that underlies autism-relevant synaptic and behavioral changes in mice” by Yun-wu Zhang et al., PLOS Biology.
Abstract
Mdga2 deficiency leads to an aberrant activation of BDNF/TrkB signaling that underlies autism-relevant synaptic and behavioral changes in mice
MDGA2 (memprin/A5/mu domain–containing glycosylphosphatidylinositol anchor 2) functions as a suppressor of excitatory synapses, and MDGA2 mutations have been linked to autism spectrum disorder. The precise physiological role of MDGA2 and the mechanisms by which MDGA2 deficiency contributes to ASD have not been fully defined.
This study confirms that Mdga2+/− mice display increased excitatory synaptic transmission and autism-relevant behaviors, and it identifies aberrant activation of BDNF/TrkB signaling in these animals. MDGA2 binds TrkB via its MAM domain, competing with BDNF for receptor binding. Both loss of MDGA2 and the ASD-associated V930I MDGA2 mutation enhance BDNF/TrkB signaling activity.
Critically, inhibiting BDNF/TrkB signaling—either with a small-molecule inhibitor or with an MDGA2-derived peptide—reduces the elevated AMPA receptor–mediated excitatory synaptic activity and mitigates social deficits in MDGA2-deficient mice. These results highlight a novel MDGA2–BDNF/TrkB–dependent mechanism that regulates synaptic function and identify a potential therapeutic target for ASD.