An Excitatory Loop with Astrocytes Contributes to Drive Neurons to Seizure Threshold

Gómez-Gonzalo, Marta; Losi, Gabriele; Chiavegato, Angela; Zonta, Micaela; Cammarota, Mario; Brondi, Marco; Vetri, Francesco; Uva, Laura; Pozzan, Tullio; Curtis, Marco de; Ratto, Gian Michele; Carmignoto, Giorgio

doi:10.1371/journal.pbio.1000352

Cited by 195 publications

(224 citation statements)

References 63 publications

Supporting

Mentioning

202

Contrasting

Order By: Relevance

“…BAPTA can cross gap junctions between astrocytes and spread through the astrocyte syncytium to inhibit calcium in many astrocytes, as demonstrated by the decrease in calcium transients in neighboring astrocytes (Fig. 4 B, E, and F) (29,38). We confirmed that astrocytic gap junctions were not blocked when patching with BAPTA by measuring the spread of the biocytin reaction product after fixation (Fig.…”

Section: Stimulation Of Individual Astrocytes Increases Network Astrosupporting

confidence: 64%

Astrocytic regulation of cortical UP states

Poskanzer

Yuste²

2011

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

182

162

View full text Add to dashboard Cite

The synchronization of neuronal assemblies during cortical UP states has been implicated in computational and homeostatic processes, but the mechanisms by which this occurs remain unknown. To investigate potential roles of astrocytes in synchronizing cortical circuits, we electrically activated astrocytes while monitoring the activity of the surrounding network with electrophysiological recordings and calcium imaging. Stimulating a single astrocyte activates other astrocytes in the local circuit and can trigger UP state synchronizations of neighboring neurons. Moreover, interfering with astrocytic activity with intracellular injections of a calcium chelator into individual astrocytes inhibits spontaneous and stimulated UP states. Finally, both astrocytic activity and neuronal UP states are regulated by purinergic signaling in the circuit. These results demonstrate that astroglia can play a causal role in regulating the synchronized activation of neuronal ensembles.T he transient synchrony of distributed groups of neurons is an important operational characteristic of the cerebral cortex for sensory processing and internal computational functions (1-4). One important type of synchrony-the multineuronal, network-driven fluctuations in membrane potential known as UP and DOWN states-occurs in neocortex both in vitro and in vivo (5-11). During UP states, neurons are depolarized for up to hundreds of milliseconds, sometimes firing barrages of action potentials (12). The function of these UP states is unknown, although they underlie synchronization among distant cortical territories (13). UP states in vivo are observed at similar frequencies as the "resting" spontaneous activity that is evident in functional MRI and EEG recordings from human subjects when not involved in sensory motor tasks (14-16), so they may be a cellular basis of this activity.The mechanisms by which UP states occur remain unclear, although recurrent excitatory activity is important (6, 9). Because astrocytes regulate extracellular glutamate (17), we explored their effects on cortical UP states using electrophysiology and population calcium imaging. The effects of astroglia on synaptic transmission and plasticity have been intensely studied, but their role in coherent function of the circuit has received much less attention, even though glia constitute almost half of all of the cells in the adult human brain (17) and are well-suited for longrange, network-wide signaling. Astrocytes also tile the cortex with near-complete coverage (18,19), are connected into an extensive syncytium via gap junctions (20,21), and communicate by intercellular calcium signaling (22), and processes from a single astrocyte can contact up to tens of thousands of synapses (18), making them attractive candidates for mediating neuronal synchronization. Here we describe a role of astrocytes in the cortical circuit, demonstrating their importance in the modulation of neuronal UP states.Results UP States Are Network-Wide Events. We performed whole-cell patch clamping of neurons i...

show abstract

Section: Stimulation Of Individual Astrocytes Increases Network Astrosupporting

confidence: 64%

Astrocytic regulation of cortical UP states

Poskanzer

Yuste²

2011

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

182

162

View full text Add to dashboard Cite

show abstract

“…It is surprising that SE was not affected in dnSNARE mice given that recent in situ studies suggest that astrocytic calcium signals could contribute to the initiation of seizure during SE through a glutamate-mediated mechanism (21). However, this mechanism operates at the seizure focus by lowering the epileptic threshold and becomes dispensable in the presence of saturating stimuli (21). It is likely that our pilocarpine treatment is a saturating stimulus that masks this threshold-modulating mechanism.…”

Section: Discussionmentioning

confidence: 98%

Astrocyte control of synaptic NMDA receptors contributes to the progressive development of temporal lobe epilepsy

Clasadonte

Dong

Hines

2013

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

View full text Add to dashboard Cite

Astrocytes modulate neuronal activity, synaptic transmission, and behavior by releasing chemical transmitters in a process termed gliotransmission. Whether this process impacts epilepsy in vivo is not known. We show that genetic impairment of transmitter release from astrocytes by the expression of a glial dominantnegative SNARE domain in mice reduced epileptiform activity in situ, delayed seizure onset after pilocarpine-induced status epilepticus, and attenuated subsequent progressive increase in seizure frequency in vivo. The reduced seizure frequency was accompanied by attenuation of hippocampal damage and behavioral deficits. As the delay in seizure onset and the reduced seizure frequency were mimicked by intracerebroventricular delivery of the NMDA receptor (NMDAR) antagonist D-(-)-2-amino-5-phosphonopentanoate in WT littermates and because dominant-negative SNARE expression leads to a hypofunction of synaptic NMDARs, we conclude that astrocytes modulate epileptogenesis, recurrent spontaneous seizures, and pathophysiological consequences of epilepsy through a pathway involving NMDARs.glia-to-neuron signaling | pilocarpine mouse | electroencephalography | hippocampus | interictal spikes T emporal lobe epilepsy (TLE), one of the most common neurological disorders, which affects 1% of the population worldwide, is characterized by the occurrence of recurring unprovoked spontaneous seizures. Unfortunately, seizures in 30% of patients with TLE are not controlled by anticonvulsant agents, drugs that are directed to neuronal targets. In this case, patients may undergo resective epilepsy surgery to become seizure-free (1).Emerging evidence suggests a critical role for the glial cells, astrocytes, in epilepsy (2, 3). Astrocytes play an important role in maintaining central nervous system function by releasing gliotransmitters, including glutamate, D-serine, and ATP (4). Whether gliotransmission contributes to epilepsy in vivo has not been established. It has recently been shown that gliotransmission regulates the trafficking and surface expression of the neuronal N-methyl-D-aspartate receptor (NMDAR) subunits 2A and 2B (5, 6). Because of the importance of NMDARs in epilepsy (7), we hypothesize that astrocytes modulate epileptic seizures by regulating these receptors. To test this hypothesis, we used astrocytespecific molecular genetics in mice to inhibit transmitter release from astrocytes, along with the in vivo pilocarpine model of TLE, long-term continuous video EEG, and an in situ hippocampal slice model of epilepsy.We show that genetic impairment of transmitter release from astrocytes by the expression of glial dominant-negative SNARE (dnSNARE) (8) delayed the onset of spontaneous recurrent seizures (SRSs) and attenuated the progressive increase in frequency of SRSs, hippocampal sclerosis, and the appearance of aberrant open-field behaviors. Similarly, chemically induced epileptiform activity in situ was attenuated by the expression of astrocytic dnSNARE. The ability of dnSNARE to reduce epileptiform activity in...

show abstract

“…A parsimonious explanation to resolve this controversy could be that astrocytic effect only becomes relevant at near-threshold condi- tions, as suggested by a recent elegant study investigating seizure initiation (Gó mez-Gonzalo et al, 2010). Whisker stimulation provides input strength of physiological range to the cerebral cortex that may be on the threshold of plasticity induction, and therefore astrocytic mechanisms may have been critical for plasticity induction in our paradigm.…”

Section: Discussionmentioning

confidence: 99%

Astrocyte Calcium Signaling Transforms Cholinergic Modulation to Cortical PlasticityIn Vivo

Takata¹,

Mishima

Hisatsune³

et al. 2011

J. Neurosci.

344

341

View full text Add to dashboard Cite

An Excitatory Loop with Astrocytes Contributes to Drive Neurons to Seizure Threshold

Abstract: Studies in rodent brain slices suggest that seizures in focal epilepsies are sustained and propagated by the reciprocal interaction between neurons and astroglial cells

Cited by 195 publications

References 63 publications

Astrocytic regulation of cortical UP states

Astrocytic regulation of cortical UP states

Astrocyte control of synaptic NMDA receptors contributes to the progressive development of temporal lobe epilepsy

Astrocyte Calcium Signaling Transforms Cholinergic Modulation to Cortical PlasticityIn Vivo

Contact Info

Product

Resources

About