An astrocyte-dependent mechanism for neuronal rhythmogenesis

Morquette, Philippe; Verdier, Dorly; Kadala, Aklesso; Féthière, James; Philippe, Antony G.; Robitaille, Richard; Kolta, Arlette

doi:10.1038/nn.4013

Cited by 137 publications

(197 citation statements)

References 49 publications

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“…Whereas the expression of NMDARs and L-VGCCs in astrocytes has been debated, our study is in line with previous studies reporting of the presence of these channels in astrocytes (43)(44)(45)(46)(47)(48)50). With respect to astrocyte NMDARs, we find that applying NMDA in the presence of TTX to prevent synaptic transmission directly triggers astrocyte membrane depolarization, and this depolarization is compromised by intracellularly infusing MK-801 or deleting GRIN1 in astrocytes.…”

Section: Discussionsupporting

confidence: 92%

“…5A), we observed a large and slow depolarization of the astrocyte membrane potential (peak depolarization, 30.67 ± 0.59 mV, n = 12; Fig. 5 C and D), which was in agreement with previous studies (46,50). In addition, observation of the NMDA response despite of the low resting astrocyte membrane potential and in the presence of 1.5 mM extracellular Mg 2+ was reminiscent of the weak Mg 2+ block found for NMDARs expressed by cortical astrocytes (54).…”

Section: Activation Of Astrocyte Nmdars Depolarizes Astrocyte Membranesupporting

confidence: 93%

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Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Letellier

Park

Chater

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

117

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Dendrites are neuronal structures specialized for receiving and processing information through their many synaptic inputs. How input strengths are modified across dendrites in ways that are crucial for synaptic integration and plasticity remains unclear. We examined in single hippocampal neurons the mechanism of heterosynaptic interactions and the heterogeneity of synaptic strengths of pyramidal cell inputs. Heterosynaptic presynaptic plasticity that counterbalances input strengths requires N-methyl-D-aspartate receptors (NMDARs) and astrocytes. Importantly, this mechanism is shared with the mechanism for maintaining highly heterogeneous basal presynaptic strengths, which requires astrocyte Ca 2+ signaling involving NMDAR activation, astrocyte membrane depolarization, and L-type Ca 2+ channels. Intracellular infusion of NMDARs or Ca 2+-channel blockers into astrocytes, conditionally ablating the GluN1 NMDAR subunit, or optogenetically hyperpolarizing astrocytes with archaerhodopsin promotes homogenization of convergent presynaptic inputs. Our findings support the presence of an astrocytedependent cellular mechanism that enhances the heterogeneity of presynaptic strengths of convergent connections, which may help boost the computational power of dendrites.synapse heterogeneity | synaptic strength | astrocyte | hippocampal neuron | heterosynaptic plasticity A n enduring challenge in neurobiology is to understand how neurons set the strengths of their numerous synapses to efficiently process and store different information while maintaining network homeostasis. Electrophysiology and imaging approaches have revealed that synapses display a high degree of functional heterogeneity, even for those sharing the same axon or dendrite (1-3). The observation that synaptic strengths are heterogeneous, in turn, suggests that synapses can operate independently from one another. Accordingly, many studies have demonstrated the input-specificity of Hebbian and also of homeostatic forms of synaptic plasticity, where synaptic changes are restricted to inputs whose activity is altered (4-6). Nevertheless, such a synapse-autonomous behavior could potentially compromise the global network homeostasis by biasing the overall activity toward excitation or depression, and to overcome this issue, it has been proposed that distinct inputs cooperate by coordinating their relative strengths through heterosynaptic interactions (7-9). In support of the idea that synapses behave as interdependent rather than isolated functional units, the restriction of synaptic strength changes to active inputs has been demonstrated to break down at times, with the induction of synaptic plasticity in the stimulated input accompanying either synaptic depression or potentiation of the nonstimulated inputs (10-13). In a highly studied plasticity paradigm of long-term potentiation (LTP) at hippocampal Schaffer collateral-CA1 synapses, tetanic stimulation that induces LTP is often accompanied by presynaptic long-term depression (LTD) of nonstimulated Schaffer collat...

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Section: Discussionsupporting

confidence: 92%

Section: Activation Of Astrocyte Nmdars Depolarizes Astrocyte Membranesupporting

confidence: 93%

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Letellier

Park

Chater

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

117

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“…S100-induced modifications of intracellular Ca 2+ in astrocytes (Barger and Van Eldik, 1992) and in neurons by activation of RAGE receptors (Huttunen et al, 2000) appear to be involved in the modulation of synaptic plasticity. S100β released by astrocytes may also promotes changes in neuronal rhythms that are relevant for seizure onset (Morquette et al, 2015;Sakatani et al, 2008), and RAGE receptors areimplicated in both cognitive impairments (Mazarati et al, 2011) and epileptogenesis (Iori et al, 2013). In this context, there is increasing evidence that activated astrocytes play a key role in neuronal network hyperexcitability underlying seizures (Devinsky et al, 2013;Robel et al, 2015).…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Cognitive deficits and brain myo-Inositol are early biomarkers of epileptogenesis in a rat model of epilepsy

Pascente

Frigerio

Rizzi

et al. 2016

Neurobiology of Disease

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Cognitive deficits and brain myoInositol are early biomarkers of epileptogenesis in a rat model of epilepsy, Neurobiology of Disease (2016Disease ( ), doi: 10.1016Disease ( /j.nbd.2016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A C C E P T E DM A N U S C R I P T ACCEPTED MANUSCRIPT AbstractOne major unmet clinical need in epilepsy is the identification of therapies to prevent or arrest epilepsy development in patients exposed to a potential epileptogenic insult. The development of such treatments has been hampered by the lack of non-invasive biomarkers that could be used to identify the patients at-risk, thereby allowing to design affordable clinical studies. Our goal was to test the predictive value of cognitive deficits and brain astrocyte activation for the development of epilepsy following a potential epileptogenic injury. We used a model of epilepsy induced by pilocarpine-evoked status epilepticus (SE) in 21-day old rats where 60-70% of animals develop spontaneous seizures after around 70 days, although SE is similar in all rats. Learning was evaluated in the Morris water-maze at days 15 and 65 post-SE, each time followed by proton magnetic resonance spectroscopy for measuring hippocampal myo-Inositol levels, a marker of astrocyte activation. Rats were video-EEG monitored for two weeks at seven months post-SE to detect spontaneous seizures, then brain histology was done. Behavioral and imaging data were retrospectively analysed in epileptic rats and compared with non epileptic and control animals. Rats displayed spatial learning deficits within three weeks from SE. However, only epilepsy-prone rats showed accelerated forgetting and reduced learning rate compared to both rats not developing epilepsy and controls. These deficits were associated with reduced hippocampal neurogenesis. myoInositol levels increased transiently in the hippocampus of SE-rats not developing epilepsy while this increase persisted until spontaneous seizures onset in epilepsy-prone rats, being associated with a local increase in S100-positive astrocytes. Neuronal cell loss was similar in all SE-rats. Our data show that behavioral deficits, together with a non-invasive marker of astrocyte activation, predict which rats develop epilepsy after an acute injury. These measures have potential clinical relevance for identifying individuals at-risk for developing epilepsy following exposure to epileptogenic insults, and consequently, for designing adequately powered antiepileptogenesis trials.

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“…Beyond species differences in channels, differences in intracellular or extracellular regulation of Ca 2+ levels by intracellular mechanisms or astrocytes (e.g. Morquette et al, 2015) could affect circuit properties.…”

Section: Intrinsic Cellular Contributions: Ion Channels and Membrane mentioning

confidence: 99%

Evolution of vocal patterns: tuning hindbrain circuits during species divergence

Barkan

Zornik

Kelley

2016

Journal of Experimental Biology

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The neural circuits underlying divergent courtship behaviors of closely related species provide a framework for insight into the evolution of motor patterns. In frogs, male advertisement calls serve as unique species identifiers and females prefer conspecific to heterospecific calls. Advertisement calls of three relatively recently (∼8.5 Mya) diverged species -Xenopus laevis, X. petersii and X. victorianusinclude rapid trains of sound pulses (fast trills). We show that while fast trills are similar in pulse rate (∼60 pulses s) across the three species, they differ in call duration and period (time from the onset of one call to the onset of the following call). Previous studies of call production in X. laevis used an isolated brain preparation in which the laryngeal nerve produces compound action potentials that correspond to the advertisement call pattern (fictive calling). Here, we show that serotonin evokes fictive calling in X. petersii and X. victorianus as it does in X. laevis. As in X. laevis, fictive fast trill in X. petersii and X. victorianus is accompanied by an N-methyl-D-aspartate receptordependent local field potential wave in a rostral hindbrain nucleus, DTAM. Across the three species, wave duration and period are strongly correlated with species-specific fast trill duration and period, respectively. When DTAM is isolated from the more rostral forebrain and midbrain and/or more caudal laryngeal motor nucleus, the wave persists at species-typical durations and periods. Thus, intrinsic differences within DTAM could be responsible for the evolutionary divergence of call patterns across these related species.

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An astrocyte-dependent mechanism for neuronal rhythmogenesis

Cited by 137 publications

References 49 publications

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Cognitive deficits and brain myo-Inositol are early biomarkers of epileptogenesis in a rat model of epilepsy

Evolution of vocal patterns: tuning hindbrain circuits during species divergence

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