Endocannabinoid signaling in synaptic function

Abstract

In the last decades, astrocytes have emerged as important regulatory cells actively involved in brain function by exchanging signaling with neurons. The endocannabinoid (eCB) signaling is widely present in many brain areas, being crucially involved in multiple brain functions and animal behaviors. The present review presents and discusses current evidence demonstrating that astrocytes sense eCBs released during neuronal activity and subsequently release gliotransmitters that regulate synaptic transmission and plasticity. The eCB signaling to astrocytes and the synaptic regulation mediated by astrocytes activated by eCBs are complex phenomena that exhibit exquisite spatial and temporal properties, a wide variety of downstream signaling mechanisms, and a large diversity of functional synaptic outcomes. Studies investigating this topic have revealed novel regulatory processes of synaptic function, like the lateral regulation of synaptic transmission and the active involvement of astrocytes in the spike-timing dependent plasticity, originally thought to be exclusively mediated by the coincident activity of pre- and postsynaptic neurons, following Hebbian rules for associative learning. Finally, the critical influence of astrocyte-mediated eCB signaling on animal behavior is also discussed.

Keywords: 2-AG; CB1receptor; anandamide; astrocytes; endocannabinoids; synaptic plasticity.

FIGURE 1

Endocannabinoids induce DSE and eSP signaling to neurons and astrocytes. (a) (1) The increase of the activity in the presynaptic terminal (2) induces the release of eCBs. (3) Binding of eCBs to the presynaptic CB₁R produces the decrease in the glutamate release inducing depolarization‐induced suppression of excitation (DSE)(4). (3) Likewise, the interaction of eCBs to the astrocytic CB₁R (4) increase the mobilization of calcium from the internal stores and subsequently the exocytosis of glitransmitter glutamate and, in turn, (5) the interaction with presynaptic mGluRI in the heteroneuronal synapse generating excitatory short potentiation (eSP)(6). (b) Representative EPSC traces before, after neuronal depolarization (ND) and during recovery, showing DSE (upper traces) and eSP (bottom traces)