| First Author | Mendez-Vazquez H | Year | 2023 |
| Journal | Proc Natl Acad Sci U S A | Volume | 120 |
| Issue | 22 | Pages | e2300773120 |
| PubMed ID | 37216537 | Mgi Jnum | J:342969 |
| Mgi Id | MGI:7561466 | Doi | 10.1073/pnas.2300773120 |
| Citation | Mendez-Vazquez H, et al. (2023) The autism-associated loss of delta-catenin functions disrupts social behavior. Proc Natl Acad Sci U S A 120(22):e2300773120 |
| abstractText | delta-catenin is expressed in excitatory synapses and functions as an anchor for the glutamatergic AMPA receptor (AMPAR) GluA2 subunit in the postsynaptic density. The glycine 34 to serine (G34S) mutation in the delta-catenin gene has been found in autism spectrum disorder (ASD) patients and results in loss of delta-catenin functions at excitatory synapses, which is presumed to underlie ASD pathogenesis in humans. However, how the G34S mutation causes loss of delta-catenin functions to induce ASD remains unclear. Here, using neuroblastoma cells, we identify that the G34S mutation increases glycogen synthase kinase 3beta (GSK3beta)-dependent delta-catenin degradation to reduce delta-catenin levels, which likely contributes to the loss of delta-catenin functions. Synaptic delta-catenin and GluA2 levels in the cortex are significantly decreased in mice harboring the delta-catenin G34S mutation. The G34S mutation increases glutamatergic activity in cortical excitatory neurons while it is decreased in inhibitory interneurons, indicating changes in cellular excitation and inhibition. delta-catenin G34S mutant mice also exhibit social dysfunction, a common feature of ASD. Most importantly, pharmacological inhibition of GSK3beta activity reverses the G34S-induced loss of delta-catenin function effects in cells and mice. Finally, using delta-catenin knockout mice, we confirm that delta-catenin is required for GSK3beta inhibition-induced restoration of normal social behavior in delta-catenin G34S mutant animals. Taken together, we reveal that the loss of delta-catenin functions arising from the ASD-associated G34S mutation induces social dysfunction via alterations in glutamatergic activity and that GSK3beta inhibition can reverse delta-catenin G34S-induced synaptic and behavioral deficits. |
