The goal of this project is to explore previously-unknown interactions between brain-derived neurotrophic factor (BDNF) and the endocannabinoid system in the cerebral cortex. Both BDNF and endocannabinoids are highly expressed throughout the sensory, motor, and association cortices, and there is a striking overlap of expression of trkB neurotrophin receptors and type 1 cannabinoid (CB1) receptors across cortical layers, with highest levels of expression in cortical layers 2/3 and 5. Disruption f either of these neuromodulatory systems has been implicated in several neurologic and psychiatric diseases, including anxiety, depression, schizophrenia, and seizure disorders, and both systems are currently major targets for the development of novel therapeutics. We found that the effects of BDNF at inhibitory cortical synapses are mediated by the BDNF-induced mobilization of endocannabinoids acting at presynaptic CB1 receptors. The proposed studies will explore the signaling mechanisms underlying BDNF-evoked synthesis and release of endocannabinoids at inhibitory synapses using electrophysiological, molecular biological, and pharmacological approaches. The proposed studies will also extend these findings to examine BDNF-cannabinoid interactions at excitatory synapses, and explore the functional relevance of these interactions in regulating activity-dependent synaptic plasticity. Knowledge gained from these studies will provide insights into the regulation and interdependence of BDNF and endocannabinoid signaling. New mechanistic insights regarding the interaction between these neuromodulators could provide the basis for novel therapeutic approaches to neurologic and psychiatric disease.

Public Health Relevance

Neurotrophins and endocannabinoids have been implicated in the pathophysiology of a wide range of disorders, including anxiety, depression, multiple sclerosis, seizure disorders, and neuropathic pain. The knowledge gained from the proposed studies on interactions between these systems could provide the basis for novel therapeutic strategies for neurologic and psychiatric disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH094896-01A1
Application #
8387922
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Nadler, Laurie S
Project Start
2012-08-01
Project End
2017-04-30
Budget Start
2012-08-01
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$377,655
Indirect Cost
$127,655
Name
University of Connecticut
Department
Neurosciences
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Fink, James J; Robinson, Tiwanna M; Germain, Noelle D et al. (2017) Disrupted neuronal maturation in Angelman syndrome-derived induced pluripotent stem cells. Nat Commun 8:15038
Zhao, Liangfang; Yeh, Mason Li-Wen; Levine, Eric S (2015) Role for Endogenous BDNF in Endocannabinoid-Mediated Long-Term Depression at Neocortical Inhibitory Synapses eNeuro 2:
Zhao, Liangfang; Levine, Eric S (2014) BDNF-endocannabinoid interactions at neocortical inhibitory synapses require phospholipase C signaling. J Neurophysiol 111:1008-15