# Synaptic transport of endocannabinoids in the brain

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2024 · $603,036

## Abstract

Project Summary
The endocannabinoid (eCB) system plays a key role in regulating synaptic function in the brain. Dysfunction of
eCB signaling contributes to numerous psychiatric and neurological disorders including anxiety, depression, and
autism. Consequently, the development of treatments for disorders involving eCB dysfunction requires a
thorough understanding of the mechanisms regulating eCB signaling in the brain. It is well-established that
physiological and/or pathological activation of postsynaptic neurons leads to the biosynthesis and release of the
eCB 2-arachidonoylglycerol (2-AG). Once released, 2-AG traverses the synaptic cleft and activates cannabinoid
receptors located on presynaptic axon terminals, which mediate its behavioral and physiological effects.
Although considerable progress has been made in elucidating how 2-AG signaling controls synaptic function and
behavioral outputs, the mechanism(s) governing synaptic 2-AG transport remains unknown, highlighting a major
gap in our fundamental understanding of 2-AG signaling in the brain. The lipophilic nature of 2-AG limits its
diffusion across the synapse, suggesting the existence of a carrier(s) that facilitates 2-AG transport to permit
cannabinoid receptor activation. Identification of a synaptic 2-AG carrier would not only greatly enhance our
basic understanding of 2-AG signaling but could also lead to the discovery of a new therapeutic target(s) to treat
disorders involving eCB dysfunction. To that end, our group has recently identified fatty acid binding proteins
(FABPs) as intracellular carriers for eCBs. In this application, we will build upon this progress and test the novel
hypothesis that FABP5, secreted by astrocytes, functions as a synaptic carrier that is essential for 2-AG signaling
in multiple brain areas. In Aim 1, we will employ complementary pharmacological and genetic approaches to test
the hypothesis that FABP5 mediates retrograde 2-AG transport at inhibitory and excitatory synapses in the
hippocampus and ventral tegmental area, brain areas involved in cognitive and emotional regulation. In Aim 2,
we will employ our novel FABP5Flox/Flox mice to delineate the roles of astrocytic and neuronal FABP5 in controlling
synaptic 2-AG transport. Aim 3 will characterize the contributions of intracellular and secreted FABP5 in
mediating 2-AG transport at hippocampal and ventral tegmental area synapses. Successful completion of this
proposal will position FABP5 as a synaptic carrier for 2-AG at central synapses, which will greatly enhance our
basic understanding of eCB signaling and may facilitate the development of future therapeutics targeting
disorders involving eCB dysfunction.

## Key facts

- **NIH application ID:** 10770534
- **Project number:** 5R01MH122461-04
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** SAMIR HAJ-DAHMANE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $603,036
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10770534

## Citation

> US National Institutes of Health, RePORTER application 10770534, Synaptic transport of endocannabinoids in the brain (5R01MH122461-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10770534. Licensed CC0.

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