While neurons principally mediate brain function, astrocytes are emerging as cells with important neuromodulatory actions in brain physiology. In addition to homeostatic roles, astrocytes respond to ...neurotransmitters with calcium transients stimulating the release of gliotransmitters that regulate synaptic and neuronal functions. We investigated astrocyte-neuronal network interactions in vivo by combining two-photon microscopy to monitor astrocyte calcium and electrocorticogram to record neuronal network activity in the somatosensory cortex during sensory stimulation. We found astrocytes respond to sensory stimuli in a stimulus-dependent manner. Sensory stimuli elicit a surge of neuronal network activity in the gamma range (30-50 Hz) followed by a delayed astrocyte activity that dampens the steady-state gamma activity. This sensory-evoked gamma activity increase is enhanced in transgenic mice with impaired astrocyte calcium signaling and is decreased by pharmacogenetic stimulation of astrocytes. Therefore, cortical astrocytes respond to sensory inputs and regulate sensory-evoked neuronal network activity maximizing its dynamic range.
Dopamine is involved in physiological processes like learning and memory, motor control and reward, and pathological conditions such as Parkinson’s disease and addiction. In contrast to the extensive ...studies on neurons, astrocyte involvement 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 enhanced by amphetamine. In brain slices, synaptically released dopamine increases astrocyte Ca2+, stimulates ATP/adenosine release, and depresses excitatory synaptic transmission through activation of presynaptic A1 receptors. Amphetamine depresses neurotransmission through stimulation of astrocytes and the consequent A1 receptor activation. Furthermore, astrocytes modulate the acute behavioral psychomotor effects of amphetamine. Therefore, astrocytes mediate the dopamine- and amphetamine-induced synaptic regulation, revealing a novel cellular pathway in the brain reward system.
•Astrocytes in the Nucleus Accumbens respond to synaptic dopamine in vivo•Astrocytes mediate the synaptic regulation induced by dopamine and amphetamine•Amphetamine-induced enhancement in locomotion activity is modulated by astrocytes
Corkrum et al. report that astrocyte activity is required for dopamine- and amphetamine-evoked synaptic regulation and amphetamine-induced locomotor effects. Their study reveals astrocytes as active components of dopaminergic signaling and the brain reward system.
Cortical neuron-astrocyte communication in response to peripheral sensory stimulation occurs in a topographic-, frequency-, and intensity-dependent manner. However, the contribution of this ...functional interaction to the processing of sensory inputs and consequent behavior remains unclear. We investigate the role of astrocytes in sensory information processing at circuit and behavioral levels by monitoring and manipulating astrocytic activity in vivo. We show that astrocytes control the dynamic range of the cortical network activity, optimizing its responsiveness to incoming sensory inputs. The astrocytic modulation of sensory processing contributes to setting the detection threshold for tactile and thermal behavior responses. The mechanism of such astrocytic control is mediated through modulation of inhibitory transmission to adjust the gain and sensitivity of responding networks. These results uncover a role for astrocytes in maintaining the cortical network activity in an optimal range to control behavior associated with specific sensory modalities.
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•Astrocytes adjust the dynamic range of cortical sensory circuits•Astrocyte loss and gain of function affect cortical response and input gain•Disrupting basal astrocyte Ca2+ impairs detection of tactile and thermal inputs•Astrocytes contribute to sensory processing by modulating inhibitory transmission
Miguel-Quesada et al. report that cortical astrocytes increase the efficiency or cortical neurons and optimize the processing of sensory information by adjusting the dynamic range of cortical responses to sensory inputs. Such astrocytic modulation contributes to setting the detection threshold for tactile and thermal behavior responses.
Mesopic flash electroretinography (fERG) as a tool to identify N-methyl-d-aspartate receptor (NMDAR) hypofunction in subjects with schizophrenia shows great potential. We report the first fERG study ...in a genetic mouse model of schizophrenia characterized by NMDAR hypofunction from gene silencing of serine racemase (SR) expression (SR-/-), an established risk gene for schizophrenia. We analyzed fERG parameters under various background light adaptations to determine the most significant variables to allow for early identification of people at risk for schizophrenia, prior to onset of psychosis. SR is a risk gene for schizophrenia, and negative and cognitive symptoms antedate the onset of psychosis that is required for diagnosis.
The scotopic, photopic, and mesopic fERGs were analyzed in male and female mice in both SR-/- and wild-type (WT) mice and also analyzed for sex differences. Amplitude and implicit time of the a- and b-wave components, b-/a-wave ratio, and Fourier transform analysis were analyzed.
Mesopic a- and b-wave implicit times were significantly delayed, and b-wave amplitudes, b/a ratios, and Fourier transform were significantly decreased in the male SR-/- mice compared to WT, but not in female SR-/- mice. No significant differences were observed in photopic or scotopic fERGs between genotype.
The fERG prognostic capability may be improved by examination of background light adaptation, a larger array of light intensities, considering sex as a variable, and performing Fourier transform analyses of all waveforms. This should improve the ability to differentiate between controls and subjects with schizophrenia characterized by NMDAR hypofunction.
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.
Main Points
Gq signaling in neurons and astrocytes leads to cellular activation, but while Gi/o signaling in neurons leads to cellular inhibition, it leads to activation in astrocytes and downstream gliotransmission that modulates neuronal activity.
Synaptic transmission and its activity-dependent modulation, known as synaptic plasticity, are fundamental processes in nervous system function. Neurons may receive thousands of synaptic contacts, ...but synaptic regulation may occur only at individual or discrete subsets of synapses, which may have important consequences on the spatial extension of the modulation of synaptic information. Moreover, while several electrophysiological methods are used to assess synaptic transmission at different levels of observation, i.e., through local field potential and individual whole-cell recordings, their experimental limitations to detect synapse-specific modulation is poorly defined. We have investigated how well-known synapse-specific short-term plasticity, where some synapses are regulated and others left unregulated, mediated by astrocytes and endocannabinoid (eCB) signaling can be assessed at different observational levels. Using hippocampal slices, we have combined local field potential and whole-cell recordings of CA3-CA1 synaptic activity evoked by Schaffer collateral stimulation of either multiple or single synapses through bulk or minimal stimulation, respectively, to test the ability to detect short-term synaptic changes induced by eCB signaling. We also developed a mathematical model assuming a bimodal distribution of regulated and unregulated synapses based on realistic experimental data to simulate physiological results and to predict the experimental requirements of the different recording methods to detect discrete changes in subsets of synapses. We show that eCB-induced depolarization-induced suppression of excitation (DSE) and astrocyte-mediated synaptic potentiation can be observed when monitoring single or few synapses, but are statistically concealed when recording the activity of a large number of synapses. These results indicate that the electrophysiological methodology is critical to properly assess synaptic changes occurring in subsets of synapses, and they suggest that relevant synapse-specific regulatory phenomena may be experimentally undetected but may have important implications in the spatial extension of synaptic plasticity phenomena.
The context in which learning occurs is sufficient to reconsolidate stored memories and neuronal reactivation may be crucial to memory consolidation during sleep. The mechanisms of context-dependent ...and sleep-dependent memory (re)consolidation are unknown but involve the hippocampus. We simulated memory (re)consolidation using a connectionist model of the hippocampus that explicitly accounted for its dorsoventral organization and for CA1 proximodistal processing. Replicating human and rodent (re)consolidation studies yielded the following results. (1) Semantic overlap between memory items and extraneous learning was necessary to explain experimental data and depended crucially on the recurrent networks of dorsal but not ventral CA3. (2) Stimulus-free, sleep-induced internal reactivations of memory patterns produced heterogeneous recruitment of memory items and protected memories from subsequent interference. These simulations further suggested that the decrease in memory resilience when subjects were not allowed to sleep following learning was primarily due to extraneous learning. (3) Partial exposure to the learning context during simulated sleep (i.e., targeted memory reactivation) uniformly increased memory item reactivation and enhanced subsequent recall. Altogether, these results show that the dorsoventral and proximodistal organization of the hippocampus may be important components of the neural mechanisms for context-based and sleep-based memory (re)consolidations.
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 G
and G
GPCR activation on astroglial Ca
-based activity, gliotransmitter release, and the functional consequences on neuronal electrical activity. We found that while G
GPCR activation led to cellular activation in both neurons and astrocytes, G
GPCR activation led to cellular inhibition in neurons and cellular activation in astrocytes. Astroglial activation by either G
or G
protein-mediated signaling stimulated gliotransmitter release, which increased neuronal excitability. Additionally, activation of G
and G
DREADDs in vivo increased astrocyte Ca
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.
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