Journal article
Leptin-induced spine formation requires TrpC channels and the CaM kinase cascade in the hippocampus
The Journal of neuroscience, Vol.34(30), pp.10022-10033
07/23/2014
Handle:
https://hdl.handle.net/2376/109919
PMCID: PMC4107395
PMID: 25057204
Abstract
Leptin is a critical neurotrophic factor for the development of neuronal pathways and synaptogenesis in the hypothalamus. Leptin receptors are also found in other brain regions, including the hippocampus, and a postnatal surge in leptin correlates with a time of rapid growth of dendritic spines and synapses in the hippocampus. Leptin is critical for normal hippocampal dendritic spine formation as db/db mice, which lack normal leptin receptor signaling, have a reduced number of dendritic spines in vivo. Leptin also positively influences hippocampal behaviors, such as cognition, anxiety, and depression, which are critically dependent on dendritic spine number. What is not known are the signaling mechanisms by which leptin initiates spine formation. Here we show leptin induces the formation of dendritic protrusions (thin headless, stubby and mushroom shaped spines), through trafficking and activation of TrpC channels in cultured hippocampal neurons. Leptin-activation of the TrpC current is dose dependent and blocked by targeted knockdown of the leptin receptor. The nonselective TrpC channel inhibitors SKF96365 and 2-APB or targeted knockdown of TrpC1 or 3, but not TrpC5, channels also eliminate the leptin-induced current. Leptin stimulates the phosphorylation of CaMKIγ and β-Pix within 5 min and their activation is required for leptin-induced trafficking of TrpC1 subunits to the membrane. Furthermore, we show that CaMKIγ, CaMKK, β-Pix, Rac1, and TrpC1/3 channels are all required for both the leptin-sensitive current and leptin-induced spine formation. These results elucidate a critical pathway underlying leptin's induction of dendritic morphological changes that initiate spine and excitatory synapse formation.
Metrics
5 Record Views
Details
- Title
- Leptin-induced spine formation requires TrpC channels and the CaM kinase cascade in the hippocampus
- Creators
- Matasha Dhar - Department of Integrative Physiology and Neuroscience, and Program in Neuroscience, Washington State University, Pullman, Washington 99164, andGary A Wayman - Department of Integrative Physiology and Neuroscience, and Program in Neuroscience, Washington State University, Pullman, Washington 99164, and waymang@vetmed.wsu.edu appleyas@vetmed.wsu.eduMingyan Zhu - Department of Integrative Physiology and Neuroscience, and Program in Neuroscience, Washington State University, Pullman, Washington 99164, andTalley J Lambert - Department of Integrative Physiology and Neuroscience, and Program in Neuroscience, Washington State University, Pullman, Washington 99164, andMonika A Davare - Knight Cancer Institute, Oregon Health and Sciences University, Portland, Oregon 97239Suzanne M Appleyard - Department of Integrative Physiology and Neuroscience, and Program in Neuroscience, Washington State University, Pullman, Washington 99164, and waymang@vetmed.wsu.edu appleyas@vetmed.wsu.edu
- Publication Details
- The Journal of neuroscience, Vol.34(30), pp.10022-10033
- Academic Unit
- Integrative Physiology and Neuroscience, Department of
- Publisher
- United States
- Grant note
- DK083452 / NIDDK NIH HHS MH086032 / NIMH NIH HHS R01 MH086032 / NIMH NIH HHS R01 DK083452 / NIDDK NIH HHS
- Identifiers
- 99900547041501842
- Language
- English
- Resource Type
- Journal article