한빛사 논문
Sehyoun Yoon1, Kristoffer Myczek1, Peter Penzes1,2,3,4,*
1Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
2Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
3Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
4Northwestern University, Center for Autism and Neurodevelopment, Chicago, IL, 60611, USA
*Corresponding author
Abstract
Background
Diacylglycerol lipase α (DAGLα), 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
DAGLα wild-type (WT) 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 (AnkG cKO) and WT male mice.
Results
DAGLα modulates dendritic spine size and density, but the effects of changes in its protein level vs. enzymatic activity are different, implicating either 2-arachidonoylglycerol (2-AG)-dependent or independent mechanism. The 2-AG-independent effects are mediated by the interaction of DAGLα with ankyrin-G, a multifunctional scaffold protein implicated in psychiatric disorders. Using superresolution microscopy, we observed that they colocalize in distinct nanodomains, which correlate with spine size. In situ Proximity Ligation Assay (PLA) combined with structured illumination microscopy (SIM) reveals that DAGLα phosphorylation upon forskolin treatment enhances the interaction with ankyrin-G in spines, leading to increased spine size and decreased DAGLα surface diffusion. AnkG cKO mice show significantly decreased DAGLα-positive neurons in the forebrain. In mice, ankyrin-G is required for forskolin-dependent reversal of depression-related behavior.
Conclusion
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.
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