Astrocytic regulation of cortical UP states

Abstract

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...

Human cortical–hippocampal dialogue in wake and slow-wave sleep

“…The physiology underlying infraslow propagation over hundreds to thousands of milliseconds is also presently unknown. This mechanistic uncertainty extends to propagation of ∼1-Hz activity over hundreds of milliseconds, where prior work has implicated factors ranging from purinergic signaling to the balance in excitatory and inhibitory activity (7,35). Future work is required to resolve these questions.…”

Contribution of extrasynapticN-methyl-d-aspartate and adenosine A1 receptors in the generation of dendritic glutamate-mediated plateau potentials

“…This means that during intense excitatory glutamatergic barrages, a release of adenosine from neurons and/or glia would assist in shortening the duration of glutamatemediated plateau potentials via the opening of K þ channels [27,[59][60][61]. The release of adenosine from neurons or glial cells can act as a protective mechanism against glutamate overstimulation in two ways: (i) by inhibiting glutamate release from presynaptic terminals and (ii) by downregulating the synaptic activity level during ischaemic-like conditions [62][63][64][65] or during an UP state in slow wave sleep [22,66,67]. It was shown that extracellular concentration of adenosine tends to escalate during seizures and after stroke, possibly as a homeostatic feedback mechanism for preventing tissue damage and by acting as an endogenous anticonvulsant [68][69][70].…”

Ruthenium polypyridyl phototriggers: from beginnings to perspectives

“…The design of RuBi-GABA [18] and RuBiGlutamate [20] opened a wide spectrum of possibilities to experiment with 1P and 2P active caged versions of the most ubiquitous inhibitory and excitatory neurotransmitters. RuBi-Glutamate appears to be a superb tool to determine circuitry in dense neuronal systems [28][29][30][31][32]. On the other hand, the physiology of neuronal inhibition can be studied with the use of RuBi-GABA, the first caged GABA with 2P capabilities, necessary to address single dendritic spines [33][34][35][36].…”