Endocannabinoids at the synapse and beyond: implications for neuropsychiatric disease pathophysiology and treatment

Abstract

Endocannabinoids (eCBs) are lipid neuromodulators that suppress neurotransmitter release, reduce postsynaptic excitability, activate astrocyte signaling, and control cellular respiration. Here, we describe canonical and emerging eCB signaling modes and aim to link adaptations in these signaling systems to pathological states. Adaptations in eCB signaling systems have been identified in a variety of biobehavioral and physiological process relevant to neuropsychiatric disease states including stress-related disorders, epilepsy, developmental disorders, obesity, and substance use disorders. These insights have enhanced our understanding of the pathophysiology of neurological and psychiatric disorders and are contributing to the ongoing development of eCB-targeting therapeutics. We suggest future studies aimed at illuminating how adaptations in canonical as well as emerging cellular and synaptic modes of eCB signaling contribute to disease pathophysiology or resilience could further advance these novel treatment approaches.

Fig. 1. Cellular aspects of eCB signaling.

Schematic diagram of eCB signaling elements within synapses, astrocytes and microglia. At the synapse, eCBs are synthesized postsynaptically, through a variety of mechanisms that result in increases in intracellular calcium, and activate presynaptic CB1 receptors to mediate retrograde suppression of neurotransmitter release. AEA can also activate TRPV1 receptors to initiate postsynaptic LTD via glutamate receptor internalization. CB1 receptors expressed on astrocytes can lead to increases in calcium release and release of gliotransmitters, which can indirectly affect synaptic transmission. CB2 receptors on microglia can regulate cytokine release. CB1 receptors expressed on mitochondria can also regulate a variety of intracellular processes including cellular energetics.

Fig. 2. Stress-induced adaptations in eCB signaling.

Synaptic activity in the paraventricular hypothalamus and the amygdala is heavily modulated by stress. Excitatory neurotransmission in the neurosecretory cells of PVN is acutely suppressed by corticosterone mediated eCB release. Sustained high levels of corticosterone during repeated stress exposure leads to impairment in DSI and DSE through the reversible downregulation of CB1Rs in PVN. In the amygdala, however, DSI and LTD of GABAergic synapses are enhanced, likely by increased 2-AG signaling, despite impaired CB1R function. Conversely, stress leads to enhanced glutamate release, likely as a result of increased FAAH activity and reduction in AEA-mediated suppression of glutamate release.

Fig. 3. eCB regulation of hypothalamic feeding circuits.

a LPBN-projecting MC4R neurons withing PVN play a key role in feeding behavior and energy homeostasis and are regulated by GABAergic inputs from a variety of sources including the arcuate nucleus. b Increased food intake and reduced energy expenditure observed after 16 h fasting is associated with enhanced 2-AG mediated suppression of GABA release from its inhibitory presynaptic afferents and increased action potential frequency of MC4R PVN neurons compared to the fed mice. c Pharmacological inhibition of DAGL causes impairment in 2-AG-mediated suppression of GABA release and blocks fasting-induced increase in action potential firing of MC4R PVN neurons. Concomitantly, MC4R-selective DAGLα-KO mice demonstrate lower food intake post-fasting and increased energy expenditure.

Fig. 4. Altered eCS in a FXS model.

Hyperactive mGlu5 signalling in FMRP-KO mice leads to increased 2-AG-mediated suppression of GABA release in neurons within the striatum and the hippocampus. Desensitized CB1R receptor function is observed at glutamatergic synapses possibly due to excess 2-AG release and receptor overactivation. Additionally, mGlu5-mediated eCB-LTD is impaired in prefrontal cortex and ventral striatum of FMRP-KO mice. These impairments are associated with targeting of DAGLα away from the postsynaptic density, caused by reduction in the scaffold protein Homer, selectively enhancing 2-AG-mediated heterosynaptic suppression of GABA release. Ultimately, these eCB signaling adaptations shift excitation/inhibition balance toward excess synaptic excitation.