@article{80963d0a51b14eb7af1e4c07994f1701,
title = "Opposing retrograde and astrocyte-dependent endocannabinoid signaling mechanisms regulate lateral habenula synaptic transmission",
abstract = "The lateral habenula (LHb) encodes aversive states, and its dysregulation is implicated in neuropsychiatric disorders, including depression. The endocannabinoid (eCB) system is a neuromodulatory signaling system that broadly serves to counteract the adverse effects of stress; however, CB1 receptor signaling within the LHb can paradoxically promote anxiogenic- and depressive-like effects. Current reports of synaptic actions of eCBs in the LHb are conflicting and lack systematic investigation of eCB regulation of excitatory and inhibitory transmission. Here, we report that eCBs differentially regulate glutamatergic and GABAergic transmission in the LHb, exhibiting canonical and circuit-specific inhibition of both systems and an opposing potentiation of synaptic glutamate release mediated via activation of CB1 receptors on astrocytes. Moreover, simultaneous depression of GABA and potentiation of glutamate release increases the net excitation-inhibition ratio onto LHb neurons, suggesting a potential cellular mechanism by which cannabinoids may promote LHb activity and subsequent anxious- and depressive-like aversive states.",
keywords = "CP: Neuroscience, GABA, anxiety, astrocyte, cannabinoid, depression, endocannabinoid, glutamate, habenula",
author = "Winters, {Nathan D.} and Veronika Kondev and Niharika Loomba and Eric Delpire and Grueter, {Brad A.} and Sachin Patel",
note = "Funding Information: These studies were supported by NIH grants MH107435 (S.P.), MH119817 (S.P.), and F31MH126460 (V.K.). The Cnr1 floxed mouse generation was supported by the Integrative Neuroscience Initiative on Alcoholism ( INIA stress) grant AA9013514 (E.D.). Confocal imaging for histology was performed in part through the use of the Vanderbilt Cell Imaging Shared Resource (supported by NIH grants CA68485 , DK20593 , DK58404 , DK59637 , and EY08126 ) and the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center . The graphical abstract and schematic in Figure 3 B were created with BioRender.com . Funding Information: These studies were supported by NIH grants MH107435 (S.P.), MH119817 (S.P.), and F31MH126460 (V.K.). The Cnr1 floxed mouse generation was supported by the Integrative Neuroscience Initiative on Alcoholism (INIA stress) grant AA9013514 (E.D.). Confocal imaging for histology was performed in part through the use of the Vanderbilt Cell Imaging Shared Resource (supported by NIH grants CA68485, DK20593, DK58404, DK59637, and EY08126) and the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. The graphical abstract and schematic in Figure 3B were created with BioRender.com. N.D.W. V.K. and N.L. conducted all experiments and analyzed the data in the laboratories of B.A.G and S.P. N.D.W. B.A.G. and S.P. contributed to experimental design. E.D. generated Cnr1 floxed mice. N.D.W. and S.P. are responsible for study conception and data interpretation. N.D.W. B.A.G. and S.P wrote the manuscript. S.P. is a scientific consultant for Psy Therapeutics, Janssen Pharmaceuticals, and Jazz Pharmaceuticals unrelated to the present work. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = mar,
day = "28",
doi = "10.1016/j.celrep.2023.112159",
language = "English (US)",
volume = "42",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}