The goal of this project is to explore the functional relevance of interactions between brain-derived neurotrophic factor (BDNF) and endogenous cannabinoids (eCB) in regulating activity-dependent synaptic plasticity in the neocortex and hippocampus. Although there is growing evidence for crosstalk between BDNF and eCBs, little is known regarding potential synaptic interactions. We have previously characterized the synaptic effects of eCBs and BDNF in layer 2/3 and layer 5 of somatosensory cortex as well as the CA1 area of hippocampus, and we have recently shown that the presynaptic effects of BDNF at cortical and hippocampal inhibitory synapses are mediated by the BDNF-induced release of eCBs from postsynaptic pyramidal cells. We have also found that BDNF causes release of eCBs at excitatory synapses, and this eCB signaling mitigates the direct facilitatory effects of BDNF at these synapses. We are now poised to explore the functional relevance of these interactions in regulating activity-dependent synaptic plasticity. In particular, we will examine the interactions between endogenous BDNF-induced eCB release and activity-dependent eCB release in regulating the magnitude and direction of plasticity at excitatory and inhibitory synapses. These studies will combine electrophysiology and calcium imaging with pharmacological and genetic approaches to manipulate these signaling systems. We will also examine these signaling interactions using mice engineered to express common human single-nucleotide polymorphisms (SNPs) that affect either endogenous BDNF or anandamide levels. Importantly, we will carry out parallel studies using cultured human induced pluripotent stem cell (iPSC)-derived neurons generated from individuals who carry these same SNPs.

Public Health Relevance

Neurotrophins and endocannabinoids have been implicated in the pathophysiology of a wide range of disorders, including autism, epilepsy, multiple sclerosis, 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 Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS111986-01A1
Application #
9897089
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Mamounas, Laura
Project Start
2019-12-01
Project End
2024-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Neurosciences
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030