Cannabinoid receptors play key roles in brain function, and cannabinoid effects in brain physiology and drug-related behavior are thought to be mediated by receptors present in neurons. Neuron-astrocyte communication relies on the expression by astrocytes of neurotransmitter receptors. Yet, the expression of cannabinoid receptors by astrocytes in situ and their involvement in the neuron-astrocyte communication remain largely unknown. We show that hippocampal astrocytes express CB1 receptors that upon activation lead to phospholipase C-dependent Ca2+ mobilization from internal stores. These receptors are activated by endocannabinoids released by neurons, increasing astrocyte Ca2+ levels, which stimulate glutamate release that activates NMDA receptors in pyramidal neurons. These results demonstrate the existence of endocannabinoid-mediated neuron-astrocyte communication, revealing that astrocytes are targets of cannabinoids and might therefore participate in the physiology of cannabinoid-related addiction. They also reveal the existence of an endocannabinoid-glutamate signaling pathway where astrocytes serve as a bridge for nonsynaptic interneuronal communication.
Endocannabinoids and their receptor CB1 play key roles in brain function. Astrocytes express CB1Rs that are activated by endocannabinoids released by neurons. However, the consequences of the endocannabinoid-mediated neuron-astrocyte signaling on synaptic transmission are unknown. We show that endocannabinoids released by hippocampal pyramidal neurons increase the probability of transmitter release at CA3-CA1 synapses. This synaptic potentiation is due to CB1R-induced Ca(2+) elevations in astrocytes, which stimulate the release of glutamate that activates presynaptic metabotropic glutamate receptors. While endocannabinoids induce synaptic depression in the stimulated neuron by direct activation of presynaptic CB1Rs, they indirectly lead to synaptic potentiation in relatively more distant neurons by activation of CB1Rs in astrocytes. Hence, astrocyte calcium signal evoked by endogenous stimuli (neuron-released endocannabinoids) modulates synaptic transmission. Therefore, astrocytes respond to endocannabinoids that then potentiate synaptic transmission, indicating that astrocytes are actively involved in brain physiology.
In vivo and in vitro studies reveal that astrocytes, classically considered supportive cells for neurons, regulate synaptic plasticity in the mouse hippocampus and are directly involved in information storage.
Experience-dependent plasticity of synaptic transmission, which represents the cellular basis of learning, is accompanied by morphological changes in dendritic spines. Astrocytic processes are intimately associated with synapses, structurally enwrapping and functionally interacting with dendritic spines and synaptic terminals by responding to neurotransmitters and by releasing gliotransmitters that regulate synaptic function. While studies on structural synaptic plasticity have focused on neuronal elements, the structural-functional plasticity of astrocyte-neuron relationships remains poorly known. Here we show that stimuli inducing hippocampal synaptic LTP enhance the motility of synapse-associated astrocytic processes. This motility increase is relatively rapid, starting Ͻ5 min after the stimulus, and reaching a maximum in 20 -30 min (t (1/2) ϭ 10.7 min). It depends on presynaptic activity and requires G-protein-mediated Ca 2ϩ elevations in astrocytes. The structural remodeling is accompanied by changes in the ability of astrocytes to regulate synaptic transmission. Sensory stimuli that increase astrocyte Ca 2ϩ also induce similar plasticity in mouse somatosensory cortex in vivo. Therefore, structural relationships between astrocytic processes and dendritic spines undergo activity-dependent changes with metaplasticity consequences on synaptic regulation. These results reveal novel forms of synaptic plasticity based on structural-functional changes of astrocyte-neuron interactions.
Numerous evidence demonstrates that astrocytes, a type of glial cell, are integral functional elements of the synapses, responding to neuronal activity and regulating synaptic transmission and plasticity. Consequently, they are actively involved in the processing, transfer and storage of information by the nervous system, which challenges the accepted paradigm that brain function results exclusively from neuronal network activity, and suggests that nervous system function actually arises from the activity of neuron-glia networks. Most of our knowledge of the properties and physiological consequences of the bidirectional communication between astrocytes and neurons resides at cellular and molecular levels. In contrast, much less is known at higher level of complexity, i.e. networks of cells, and the actual impact of astrocytes in the neuronal network function remains largely unexplored. In the present article, we summarize the current evidence that supports the notion that astrocytes are integral components of nervous system networks and we discuss some functional properties of intercellular signalling in neuron-glia networks.
Endocannabinoids (eCBs) play key roles in brain function, acting as modulatory signals in synaptic transmission and plasticity. They are recognized as retrograde messengers that mediate long-term synaptic depression (LTD), but their ability to induce long-term potentiation (LTP) is poorly known. We show that eCBs induce the long-term enhancement of transmitter release at single hippocampal synapses through stimulation of astrocytes when coincident with postsynaptic activity. This LTP requires the coordinated activity of the 3 elements of the tripartite synapse: 1) eCB-evoked astrocyte calcium signal that stimulates glutamate release; 2) postsynaptic nitric oxide production; and 3) activation of protein kinase C and presynaptic group I metabotropic glutamate receptors, whose location at presynaptic sites was confirmed by immunoelectron microscopy. Hence, while eCBs act as retrograde signals to depress homoneuronal synapses, they serve as lateral messengers to induce LTP in distant heteroneuronal synapses through stimulation of astrocytes. Therefore, eCBs can trigger LTP through stimulation of astrocyte-neuron signaling, revealing novel cellular mechanisms of eCB effects on synaptic plasticity.
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