| First Author | Marshall J | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 15 | Pages | E3549-E3558 |
| PubMed ID | 29507199 | Mgi Jnum | J:261427 |
| Mgi Id | MGI:6153672 | Doi | 10.1073/pnas.1722493115 |
| Citation | Marshall J, et al. (2018) Antidepression action of BDNF requires and is mimicked by Galphai1/3 expression in the hippocampus. Proc Natl Acad Sci U S A 115(15):E3549-E3558 |
| abstractText | Stress-related alterations in brain-derived neurotrophic factor (BDNF) expression, a neurotrophin that plays a key role in synaptic plasticity, are believed to contribute to the pathophysiology of depression. Here, we show that in a chronic mild stress (CMS) model of depression the Galphai1 and Galphai3 subunits of heterotrimeric G proteins are down-regulated in the hippocampus, a key limbic structure associated with major depressive disorder. We provide evidence that Galphai1 and Galphai3 (Galphai1/3) are required for the activation of TrkB downstream signaling pathways. In mouse embryonic fibroblasts (MEFs) and CNS neurons, Galphai1/3 knockdown inhibited BDNF-induced tropomyosin-related kinase B (TrkB) endocytosis, adaptor protein activation, and Akt-mTORC1 and Erk-MAPK signaling. Functional studies show that Galphai1 and Galphai3 knockdown decreases the number of dendrites and dendritic spines in hippocampal neurons. In vivo, hippocampal Galphai1/3 knockdown after bilateral microinjection of lentiviral constructs containing Galphai1 and Galphai3 shRNA elicited depressive behaviors. Critically, exogenous expression of Galphai3 in the hippocampus reversed depressive behaviors in CMS mice. Similar results were observed in Galphai1/Galphai3 double-knockout mice, which exhibited severe depressive behaviors. These results demonstrate that heterotrimeric Galphai1 and Galphai3 proteins are essential for TrkB signaling and that disruption of Galphai1 or Galphai3 function could contribute to depressive behaviors. |
