Synaptic functions of endocannabinoid signaling in health and disease

Abstract

Endocannabinoids (eCBs) are a family of lipid molecules that act as key regulators of synaptic transmission and plasticity. They are synthetized “on demand” following physiological and/or pathological stimuli. Once released from postsynaptic neurons, eCBs typically act as retrograde messengers to activate presynaptic type 1 cannabinoid receptors (CB1) and induce short- or long-term depression of neurotransmitter release. Besides this canonical mechanism of action, recent findings have revealed a number of less conventional mechanisms by which eCBs regulate neural activity and synaptic function, suggesting that eCB-mediated plasticity is mechanistically more diverse than anticipated. These mechanisms include non-retrograde signaling, signaling via astrocytes, participation in long-term potentiation, and the involvement of mitochondrial CB1. Focusing on paradigmatic brain areas, such as hippocampus, striatum, and neocortex, we review typical and novel signaling mechanisms, and discuss the functional implications in normal brain function and brain diseases. In summary, eCB signaling may lead to different forms of synaptic plasticity through activation of a plethora of mechanisms, which provide further complexity to the functional consequences of eCB signaling.

Chronic, intermittent treatment with a cannabinoid receptor agonist impairs recognition memory and brain network functional connectivity

“…CB 1 Rs on synapses inhibit glutamatergic and GABAergic transmission, modulate different forms of synaptic plasticity and control neural oscillations that support behaviour and diverse cognitive functions, including learning and memory (Hajos et al 2000;Piomelli 2003;Kano et al 2009;Albayram et al 2016;Araque et al 2017;Lupica et al 2017). Altogether, previous data also suggest that endo-and exo-cannabinoids may induce the functional reconfiguration of neuronal and brain networks to impact on memory processing, and we now specifically addressed this possibility.…”

Localization of the cannabinoid type‐1 receptor in subcellular astrocyte compartments of mutant mouse hippocampus

“…In addition, a strong decrease in CB 1 receptors in adult mouse CA1 astrocytes has been recently observed after adolescent drinking‐in‐the‐dark ethanol intake patterns (Bonilla‐Del Río et al, ). Taken together, the subcellular compartmentalization of the CB 1 receptor in astrocytes suggests the existence of specific and precise distribution of the receptor that seems to be crucial for the functional role of the CB 1 receptor at the tripartite synapse (Araque et al, ; Araque, Castillo, Manzoni, & Tonini, ; Belluomo et al, ; Han et al, ; Metna‐Laurent & Marsicano, ; Navarrete & Araque, ; Oliveira da Cruz et al, 2015; Perez‐Alvarez et al, ).…”

“…In the present study, 11%–13% of the astrocytic mitochondrial sections were CB 1 receptor immunopositive, indicating that mtCB 1 receptors in astrocytes might play important functional roles. Indeed, their activation may impact functions in which astroglial CB 1 receptors are involved, such as metabolic activity, neuroprotection, inflammatory responses, astrocyte development and survival, synaptic transmission, plasticity or memory formation (Aguado et al, ; Araque et al, ; Araque, Castillo, Manzoni, & Tonini, ; Bosier et al, ; Han et al, ; Metna‐Laurent & Marsicano, ; Navarrete & Araque, ; Stella, ).…”

“…Therefore, restoration of CB 1 receptor expression in astrocytes and astroglial mitochondria could represent a new approach to assess the function of the tripartite synapse. CB 1 receptors in astrocytes play a key role in the two-way communication between neurons and astrocytes through rising calcium in astrocytes that modulates synaptic transmission and plasticity (Araque, Castillo, Manzoni, & Tonini, 2017;G omez-Gonzalo et al, 2015;Martin-Fernandez et al, 2017;Navarrete & Araque, 2008, 2010Navarrete et al, 2013;Navarrete, Diez, & Araque, 2014). Astroglial CB 1 receptor activation regulates astrocytic D-aspartate uptake (Shivachar, 2007) and might contribute to the brains energy supply through the control of leptin receptors expression in astrocytes (Bosier et al, 2013).…”

Sex‐specific behavioural deficits induced at early life by prenatal exposure to the cannabinoid receptor agonist WIN55, 212‐2 depend on mGlu5 receptor signalling

“…This will allow the evaluation of the possible sex-dependent effects induced by in utero WIN exposure on emotional reactivity and cognitive performance at different developmental ages before adulthood. The interaction between cannabinoids and mGlu 5 R has been extensively explored by using pharmacological, electrophysiological and anatomical approaches (Araque, Castillo, Manzoni, & Tonini, 2017;Jung et al, 2012;Katona & Freund, 2008;Lafourcade et al, 2007;Liang, Alger, & McCarthy, 2014;Won et al, 2012). Importantly, mGlu 5 R participate in the developmental regulation of the endocannabinoid system.…”