| First Author | Yoon S | Year | 2021 |
| Journal | Biol Psychiatry | Volume | 90 |
| Issue | 4 | Pages | 263-274 |
| PubMed ID | 34099188 | Mgi Jnum | J:341823 |
| Mgi Id | MGI:6741570 | Doi | 10.1016/j.biopsych.2021.03.023 |
| Citation | Yoon S, et al. (2021) cAMP Signaling-Mediated Phosphorylation of Diacylglycerol Lipase alpha Regulates Interaction With Ankyrin-G and Dendritic Spine Morphology. Biol Psychiatry 90(4):263-274 |
| abstractText | BACKGROUND: Diacylglycerol lipase alpha (DAGLalpha), a major biosynthetic enzyme for endogenous cannabinoid signaling, has emerged as a risk gene in multiple psychiatric disorders. However, its role in the regulation of dendritic spine plasticity is unclear. METHODS: DAGLalpha wild-type or point mutants were overexpressed in primary cortical neurons or human embryonic kidney 293T cells. The effects of mutated variants on interaction, dendritic spine morphology, and dynamics were examined by proximity ligation assay or fluorescence recovery after photobleaching. Behavioral tests and immunohistochemistry were performed with ankyrin-G conditional knockout and wild-type male mice. RESULTS: DAGLalpha modulated dendritic spine size and density, but the effects of changes in its protein level versus enzymatic activity were different, implicating either a 2-arachidonoylglycerol (2-AG)-dependent or -independent mechanism. The 2-AG-independent effects were mediated by the interaction of DAGLalpha with ankyrin-G, a multifunctional scaffold protein implicated in psychiatric disorders. Using superresolution microscopy, we observed that they colocalized in distinct nanodomains, which correlated with spine size. In situ proximity ligation assay combined with structured illumination microscopy revealed that DAGLalpha phosphorylation upon forskolin treatment enhanced the interaction with ankyrin-G in spines, leading to increased spine size and decreased DAGLalpha surface diffusion. Ankyrin-G conditional knockout mice showed significantly decreased DAGLalpha-positive neurons in the forebrain. In mice, ankyrin-G was required for forskolin-dependent reversal of depression-related behavior. CONCLUSIONS: Taken together, ANK3 and DAGLA, both neuropsychiatric disorder genes, interact in a complex to regulate spine morphology. These data reveal novel synaptic signaling mechanisms and potential therapeutic avenues. |
