ADGRB3-Linked Synaptic Dysfunction in Autism: Mechanistic Insights and Translational Evaluation of Fasoracetam and Novel ADGRB3 Ligands

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental condition with a strong genetic basis. Dr. Hakonarson and colleagues recently uncovered rare loss-of-function (LOF) mutations in the ADGRB3 gene, which encodes the brain-specific adhesion G-protein coupled receptor BAI3, a gene that is emerging as high-confidence risk factors for ASD. ADGRB3 plays a pivotal role in synapse formation, pruning, and neuronal morphology. Notably, recent studies demonstrate that ADGRB3 interacts with metabotropic glutamate receptor (mGluR) signaling with the latter being downregulated in autism patients with LOF variants in ADGRB3, suggesting that targeted modulation of this pathway may have therapeutic benefit in individuals with ADGRB3 LOF mutations.

Fasoracetam is a cognitive enhancer drug and selective modulator of mGluR signaling, previously investigated in clinical trials for ADHD and cognitive disorders. Given the convergence of ADGRB3 dysfunction and mGluR pathway disruption, fasoracetam represents a compelling candidate for targeted treatment in this genetically defined subgroup of ASD. Preclinical data in patient-derived neuronal models support a pathophysiological mechanism of synaptic dysfunction, aberrant pruning, axonal misrouting, and altered calcium dynamics at the synapse in ADGRB3 LOF carriers. These findings lay the foundation for translational and clinical studies aimed at modulating glutamatergic signaling to restore synaptic homeostasis in ADGRB3 loss of function patients.

Dr. Hakonarson and colleagues are conducting a suite of mechanistic studies using induced pluripotent stem cells (iPSCs) reprogrammed from peripheral blood mononuclear cells of ASD patients carrying severe ADGRB3 LOF mutations. These iPSCs have been differentiated into cortical neurons and characterized through morphological, electrophysiological, and functional assays.

The adhesion GPCR encoded by the ADGRB3 gene has been shown to be involved in synaptogenesis, dendritic spine formation and synaptic pruning, impacting excitatory/inhibitory balance across the synapse. The researchers have shown that LoF variants are associated with autism spectrum disorder (ASD) and synaptic dysfunction, including downregulation of metabotropic glutamate receptor (mGluR) signaling. These data suggest that fasoracetam, a molecule shown to modulate GABA(B), metabotropic glutamate, and cholinergic pathways with behavioral benefits in related neurodevelopmental conditions, may benefit patients with ADGRB3 LOF variants. Accordingly, this study will evaluate clinical efficacy and mechanistic biomarker effects of fasoracetam in autism subjects harboring ADGRB3 LoF variants.