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.

Dopamine is a key neurotransmitter involved in physiological processes, such as learning and memory, motor control and reward, as well as, pathological conditions, such as Parkinson's disease and drug abuse. In contrast to the extensive studies on neurons, the role of astrocytes in dopaminergic signaling remains largely unknown. Using transgenic mice, optogenetics and pharmacogenetics, we studied the role of astrocytes on the dopaminergic system. We show that in freely-behaving mice, astrocytes in the nucleus accumbens (NAc), a key reward center in the brain, respond with Ca2+ elevations to synaptically-released dopamine, a phenomenon that is enhanced by amphetamine, a psychostimulant drug that acts via increasing dopamine levels. In brain slices, synaptically-released dopamine increases astrocyte Ca2+ and stimulates the release of ATP/adenosine, which leads to excitatory synaptic depression through activation of presynaptic adenosine A1 receptors. Amphetamine depresses neurotransmission through stimulation of astrocytes and the consequent activation of presynaptic A1 receptors. Furthermore, astrocytes modulate the acute behavioral psychomotor effects of amphetamine. Therefore, astrocytes mediate the synaptic regulation induced by dopamine and amphetamine, revealing a novel cellular pathway in the brain reward system.

Interneurons are critical for proper neural network function and can activate Ca2+ signaling in astrocytes. However, the impact of the interneuron-astrocyte signaling into neuronal network operation remains unknown. Using the simplest hippocampal Astrocyte-Neuron network, i.e., GABAergic interneuron, pyramidal neuron, single CA3-CA1 glutamatergic synapse, and astrocytes, we found that interneuron-astrocyte signaling dynamically affected excitatory neurotransmission in an activity- and time-dependent manner, and determined the sign (inhibition vs potentiation) of the GABA-mediated effects. While synaptic inhibition was mediated by GABAA receptors, potentiation involved astrocyte GABAB receptors, astrocytic glutamate release, and presynaptic metabotropic glutamate receptors. Using conditional astrocyte-specific GABAB receptor (Gabbr1) knockout mice, we confirmed the glial source of the interneuron-induced potentiation, and demonstrated the involvement of astrocytes in hippocampal theta and gamma oscillations in vivo. Therefore, astrocytes decode interneuron activity and transform inhibitory into excitatory signals, contributing to the emergence of novel network properties resulting from the interneuron-astrocyte interplay.DOI: http://dx.doi.org/10.7554/eLife.20362.001

G protein‐coupled receptors (GPCRs) play key roles in intercellular signaling in the brain. Their effects on cellular function have been largely studied in neurons, but their functional consequences on astrocytes are less known. Using both endogenous and chemogenetic approaches with DREADDs, we have investigated the effects of Gq and Gi/o GPCR activation on astroglial Ca2+‐based activity, gliotransmitter release, and the functional consequences on neuronal electrical activity. We found that while GqGPCR activation led to cellular activation in both neurons and astrocytes, Gi/oGPCR activation led to cellular inhibition in neurons and cellular activation in astrocytes. Astroglial activation by either Gq or Gi/o protein‐mediated signaling stimulated gliotransmitter release, which increased neuronal excitability. Additionally, activation of Gq and Gi/o DREADDs in vivo increased astrocyte Ca2+ activity and modified neuronal network electrical activity. Present results reveal additional complexity of the signaling consequences of excitatory and inhibitory neurotransmitters in astroglia‐neuron network operation and brain function.

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.

Abnormalities in ␣-synuclein are implicated in the pathogenesis of Parkinson's disease (PD). Because ␣-synuclein is highly concentrated within presynaptic terminals, presynaptic dysfunction has been proposed as a potential pathogenic mechanism. Here, we report novel, tau-dependent, postsynaptic deficits caused by A53T mutant ␣-synuclein, which is linked to familial PD. We analyzed synaptic activity in hippocampal slices and cultured hippocampal neurons from transgenic mice of either sex expressing human WT, A53T, and A30P ␣-synuclein. Increased ␣-synuclein expression leads to decreased spontaneous synaptic vesicle release regardless of genotype. However, only those neurons expressing A53T ␣-synuclein exhibit postsynaptic dysfunction, including decreased miniature postsynaptic current amplitude and decreased AMPA to NMDA receptor current ratio. We also found that long-term potentiation and spatial learning were impaired by A53T ␣-synuclein expression. Mechanistically, postsynaptic dysfunction requires glycogen synthase kinase 3␤-mediated tau phosphorylation, tau mislocalization to dendritic spines, and calcineurin-dependent AMPA receptor internalization. Previous studies reveal that human A53T ␣-synuclein has a high aggregation potential, which may explain the mutation's unique capacity to induce postsynaptic deficits. However, patients with sporadic PD with severe tau pathology are also more likely to have early onset cognitive decline. Our results here show a novel, functional role for tau: mediating the effects of ␣-synuclein on postsynaptic signaling. Therefore, the unraveled tau-mediated signaling cascade may contribute to the pathogenesis of dementia in A53T ␣-synuclein-linked familial PD cases, as well as some subgroups of PD cases with extensive tau pathology.

Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically and neuropathologically highly related α-synucleinopathies that collectively constitute the second leading cause of neurodegenerative dementias. Genetic and neuropathological studies directly implicate α-synuclein (αS) abnormalities in PDD and DLB pathogenesis. However, it is currently unknown how αS abnormalities contribute to memory loss, particularly since forebrain neuronal loss in PDD and DLB is less severe than in Alzheimer’s disease. Previously, we found that familial Parkinson’s disease-linked human mutant A53T αS causes aberrant localization of the microtubule-associated protein tau to postsynaptic spines in neurons, leading to postsynaptic deficits. Thus, we directly tested if the synaptic and memory deficits in a mouse model of α-synucleinopathy (TgA53T) are mediated by tau. TgA53T mice exhibit progressive memory deficits associated with postsynaptic deficits in the absence of obvious neuropathological and neurodegenerative changes in the hippocampus. Significantly, removal of endogenous mouse tau expression in TgA53T mice (TgA53T/mTau−/−), achieved by mating TgA53T mice to mouse tau-knockout mice, completely ameliorates cognitive dysfunction and concurrent synaptic deficits without affecting αS expression or accumulation of selected toxic αS oligomers. Among the known tau-dependent effects, memory deficits in TgA53T mice were associated with hippocampal circuit remodeling linked to chronic network hyperexcitability. This remodeling was absent in TgA53T/mTau−/− mice, indicating that postsynaptic deficits, aberrant network hyperactivity, and memory deficits are mechanistically linked. Our results directly implicate tau as a mediator of specific human mutant A53T αS-mediated abnormalities related to deficits in hippocampal neurotransmission and suggest a mechanism for memory impairment that occurs as a consequence of synaptic dysfunction rather than synaptic or neuronal loss. We hypothesize that these initial synaptic deficits contribute to network hyperexcitability which, in turn, exacerbate cognitive dysfunction. Our results indicate that these synaptic changes present potential therapeutic targets for amelioration of memory deficits in α-synucleinopathies.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-02032-w) contains supplementary material, which is available to authorized users.

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