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.
► Endocannabinoids potentiate transmitter release at hippocampal synapses ► The synaptic potentiation requires the stimulation of astrocytes by endocannabinoids ► Astrocytes stimulated by neuronal signals modulate synaptic transmission ► Endocannabinoids depress or potentiate transmission depending on astrocyte activation
Glial cells in neuronal network function Araque, Alfonso; Navarrete, Marta
Philosophical transactions - Royal Society. Biological sciences,
08/2010, Volume:
365, Issue:
1551
Journal Article
Peer reviewed
Open access
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.
The term ‘tripartite synapse’ refers to a concept in synaptic physiology based on the demonstration of the existence of bidirectional communication between astrocytes and neurons. Consistent with ...this concept, in addition to the classic ‘bipartite’ information flow between the pre- and postsynaptic neurons, astrocytes exchange information with the synaptic neuronal elements, responding to synaptic activity and, in turn, regulating synaptic transmission. Because recent evidence has demonstrated that astrocytes integrate and process synaptic information and control synaptic transmission and plasticity, astrocytes, being active partners in synaptic function, are cellular elements involved in the processing, transfer and storage of information by the nervous system. Consequently, in contrast to the classically accepted paradigm that brain function results exclusively from neuronal activity, there is an emerging view, which we review herein, in which brain function actually arises from the coordinated activity of a network comprising both neurons and glia.
Long-term potentiation (LTP) of synaptic transmission represents the cellular basis of learning and memory. Astrocytes have been shown to regulate synaptic transmission and plasticity. However, their ...involvement in specific physiological processes that induce LTP in vivo remains unknown. Here we show that in vivo cholinergic activity evoked by sensory stimulation or electrical stimulation of the septal nucleus increases Ca²⁺ in hippocampal astrocytes and induces LTP of CA3-CA1 synapses, which requires cholinergic muscarinic (mAChR) and metabotropic glutamate receptor (mGluR) activation. Stimulation of cholinergic pathways in hippocampal slices evokes astrocyte Ca²⁺ elevations, postsynaptic depolarizations of CA1 pyramidal neurons, and LTP of transmitter release at single CA3-CA1 synapses. Like in vivo, these effects are mediated by mAChRs, and this cholinergic-induced LTP (c-LTP) also involves mGluR activation. Astrocyte Ca²⁺ elevations and LTP are absent in IP₃R2 knock-out mice. Downregulating astrocyte Ca²⁺ signal by loading astrocytes with BAPTA or GDPβS also prevents LTP, which is restored by simultaneous astrocyte Ca²⁺ uncaging and postsynaptic depolarization. Therefore, cholinergic-induced LTP requires astrocyte Ca²⁺ elevations, which stimulate astrocyte glutamate release that activates mGluRs. The cholinergic-induced LTP results from the temporal coincidence of the postsynaptic activity and the astrocyte Ca²⁺ signal simultaneously evoked by cholinergic activity. Therefore, the astrocyte Ca²⁺ signal is necessary for cholinergic-induced synaptic plasticity, indicating that astrocytes are directly involved in brain storage information.
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.
While neurons have traditionally been considered the primary players in information processing, the role of astrocytes in this mechanism has largely been overlooked due to experimental constraints. ...In this review, we propose that astrocytic ensembles are active working groups that contribute significantly to animal conduct and suggest that studying the maps of these ensembles in conjunction with neurons is crucial for a more comprehensive understanding of behavior. We also discuss available methods for studying astrocytes and argue that these ensembles, complementarily with neurons, code and integrate complex behaviors, potentially specializing in concrete functions.
Optogenetics has been widely expanded to enhance or suppress neuronal activity and it has been recently applied to glial cells. Here, we have used a new approach based on selective expression of ...melanopsin, a G‐protein‐coupled photopigment, in astrocytes to trigger Ca2+ signaling. Using the genetically encoded Ca2+ indicator GCaMP6f and two‐photon imaging, we show that melanopsin is both competent to stimulate robust IP3‐dependent Ca2+ signals in astrocyte fine processes, and to evoke an ATP/Adenosine‐dependent transient boost of hippocampal excitatory synaptic transmission. Additionally, under low‐frequency light stimulation conditions, melanopsin‐transfected astrocytes can trigger long‐term synaptic changes. In vivo, melanopsin‐astrocyte activation enhances episodic‐like memory, suggesting melanopsin as an optical tool that could recapitulate the wide range of regulatory actions of astrocytes on neuronal networks in behaving animals. These results describe a novel approach using melanopsin as a precise trigger for astrocytes that mimics their endogenous G‐protein signaling pathways, and present melanopsin as a valuable optical tool for neuron–glia studies.
Main points
Melanopsin, a mammalian G‐protein‐coupled photopigment, engages endogenous the IP3 pathway and intracellular Ca2+ signaling in astrocytes.
By releasing ATP/Ado, melanopsin‐astrocytes differently impact synaptic plasticity enhance cognitive functions.
Food addiction is linked to obesity and eating disorders and is characterized by a loss of behavioral control and compulsive food intake. Here, using a food addiction mouse model, we report that the ...lack of cannabinoid type-1 receptor in dorsal telencephalic glutamatergic neurons prevents the development of food addiction-like behavior, which is associated with enhanced synaptic excitatory transmission in the medial prefrontal cortex (mPFC) and in the nucleus accumbens (NAc). In contrast, chemogenetic inhibition of neuronal activity in the mPFC-NAc pathway induces compulsive food seeking. Transcriptomic analysis and genetic manipulation identified that increased dopamine D2 receptor expression in the mPFC-NAc pathway promotes the addiction-like phenotype. Our study unravels a new neurobiological mechanism underlying resilience and vulnerability to the development of food addiction, which could pave the way towards novel and efficient interventions for this disorder.
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