Highlights • Astrocytes are organized in extensive and plastic gap-junction mediated networks. • We evaluate their role in synaptic activity, neuronal circuit dynamics and behavior. • We discuss ...current and future tools needed to assign functions to astroglial networks. • We propose a role for astroglial networks in cognitive processes in health and disease.
Close structural and functional interactions of astrocytes with synapses play an important role in brain function. The repertoire of ways in which astrocytes can regulate synaptic transmission is ...complex so that they can both promote and dampen synaptic efficacy. Such contrasting effects raise questions regarding the determinants of these divergent astroglial functions. Recent findings provide insights into where, when and how astroglial regulation of synapses takes place by revealing major molecular and functional intrinsic heterogeneity as well as switches in astrocytes occurring during development or specific patterns of neuronal activity. Astrocytes may therefore be seen as boosters or gatekeepers of synaptic circuits depending on their intrinsic and transformative properties throughout life.
Dynamic aspects of interactions between astrocytes, neurons and the vasculature have recently been in the neuroscience spotlight. It has emerged that not only neurons but also astrocytes are ...organized into networks. Whereas neuronal networks exchange information through electrical and chemical synapses, astrocytes are interconnected through gap junction channels that are regulated by extra- and intracellular signals and allow exchange of information. This intercellular communication between glia has implications for neuroglial and gliovascular interactions and hence has added another level of complexity to our understanding of brain function.
Purinergic signaling mediated by ATP and its metabolites contributes to various brain physiological processes as well as to several pathological conditions, including neurodegenerative and ...neurological disorders, such as epilepsy. Among the different ATP release pathways, pannexin 1 channels represent one of the major conduits being primarily activated in pathological contexts. Investigations on in vitro and in vivo models of epileptiform activity and seizures in mice and human tissues revealed pannexin 1 involvement in aberrant network activity and epilepsy, and highlighted that pannexin 1 exerts a complex role. Pannexin 1 can indeed either sustain seizures through release of ATP that can directly activate purinergic receptors, or tune down epileptic activity via ATP-derived adenosine that decreases neuronal excitability. Interestingly, in-depth analysis of the literature unveils that this dichotomy is only apparent, as it depends on the model of seizure induction and the type of evoked epileptiform activity, two factors that can differentially activate pannexin 1 channels and trigger distinct intracellular signaling cascades. Here, we review the general properties and ATP permeability of pannexin 1 channels, and discuss their impact on acute epileptiform activity and chronic epilepsy according to the regime of activity and disease state. These data pave the way for the development of new antiepileptic strategies selectively targeting pannexin 1 channels in a context-dependent manner.
Astrocytes provide metabolic substrates to neurons in an activity-dependent manner. However, the molecular mechanisms involved in this function, as well as its role in synaptic transmission, remain ...unclear. Here, we show that the gap-junction subunit proteins connexin 43 and 30 allow intercellular trafficking of glucose and its metabolites through astroglial networks. This trafficking is regulated by glutamatergic synaptic activity mediated by AMPA receptors. In the absence of extracellular glucose, the delivery of glucose or lactate to astrocytes sustains glutamatergic synaptic transmission and epileptiform activity only when they are connected by gap junctions. These results indicate that astroglial gap junctions provide an activity-dependent intercellular pathway for the delivery of energetic metabolites from blood vessels to distal neurons.
Fast exchange of extracellular signals between neurons and astrocytes is crucial for synaptic function. Over the last few decades, different pathways of astroglial release of neuroactive substances ...have been proposed to modulate neurotransmission. However, their involvement in physiological conditions is highly debated. Connexins, the gap junction forming proteins, are highly expressed in astrocytes and have recently been shown to scale synaptic transmission and plasticity. Interestingly, in addition to gap junction channels, the most abundant connexin (Cx) in astrocytes, Cx43, also forms hemichannels. While such channels are mostly active in pathological conditions, they have recently been shown to regulate cognitive function. However, whether astroglial Cx43 hemichannels are active in resting conditions and regulate basal synaptic transmission is unknown. Here we show that in basal conditions Cx43 forms functional hemichannels in astrocytes from mouse hippocampal slices. We furthermore demonstrate that the activity of astroglial Cx43 hemichannels in resting states regulates basal excitatory synaptic transmission of hippocampal CA1 pyramidal cells through ATP signaling. These data reveal Cx43 hemichannels as a novel astroglial release pathway at play in basal conditions, which tunes the moment-to-moment glutamatergic synaptic transmission.
Presynaptic glutamate replenishment is fundamental to brain function. In high activity regimes, such as epileptic episodes, this process is thought to rely on the glutamate-glutamine cycle between ...neurons and astrocytes. However the presence of an astroglial glutamine supply, as well as its functional relevance in vivo in the healthy brain remain controversial, partly due to a lack of tools that can directly examine glutamine transfer. Here, we generated a fluorescent probe that tracks glutamine in live cells, which provides direct visual evidence of an activity-dependent glutamine supply from astroglial networks to presynaptic structures under physiological conditions. This mobilization is mediated by connexin43, an astroglial protein with both gap-junction and hemichannel functions, and is essential for synaptic transmission and object recognition memory. Our findings uncover an indispensable recruitment of astroglial glutamine in physiological synaptic activity and memory via an unconventional pathway, thus providing an astrocyte basis for cognitive processes.
Astroglial release of molecules is thought to actively modulate neuronal activity, but the nature, release pathway, and cellular targets of these neuroactive molecules are still unclear. Pannexin 1, ...expressed by neurons and astrocytes, form nonselective large pore channels that mediate extracellular exchange of molecules. The functional relevance of these channels has been mostly studied in brain tissues, without considering their specific role in different cell types, or in neurons. Thus, our knowledge of astroglial pannexin 1 regulation and its control of neuronal activity remains very limited, largely due to the lack of tools targeting these channels in a cell-specific way. We here show that astroglial pannexin 1 expression in mice is developmentally regulated and that its activation is activity-dependent. Using astrocyte-specific molecular tools, we found that astroglial-specific pannexin 1 channel activation, in contrast to pannexin 1 activation in all cell types, selectively and negatively regulates hippocampal networks, with their disruption inducing a drastic switch from bursts to paroxysmal activity. This decrease in neuronal excitability occurs via an unconventional astroglial mechanism whereby pannexin 1 channel activity drives purinergic signaling-mediated regulation of hyperpolarisation-activated cyclic nucleotide (HCN)-gated channels. Our findings suggest that astroglial pannexin 1 channel activation serves as a negative feedback mechanism crucial for the inhibition of hippocampal neuronal networks.
Fast calcium transients (<10 ms) remain difficult to analyse in cellular microdomains, yet they can modulate key cellular events such as trafficking, local ATP production by endoplasmic ...reticulum-mitochondria complex (ER-mitochondria complex), or spontaneous activity in astrocytes. In dendritic spines receiving synaptic inputs, we show here that in the presence of a spine apparatus (SA), which is an extension of the smooth ER, a calcium-induced calcium release (CICR) is triggered at the base of the spine by the fastest calcium ions arriving at a Ryanodyne receptor (RyR). The mechanism relies on the asymmetric distributions of RyRs and sarco/ER calcium-ATPase (SERCA) pumps that we predict using a computational model and further confirm experimentally in culture and slice hippocampal neurons. The present mechanism for which the statistics of the fastest particles arriving at a small target, followed by an amplification, is likely to be generic in molecular transduction across cellular microcompartments, such as thin neuronal processes, astrocytes, endfeets, or protrusions.
Initial biophysical studies on glial cells nearly 50 years ago identified these cells as being electrically silent. These first studies also demonstrated a large K(+) conductance, which led to the ...notion that glia may regulate extracellular K(+) levels homeostatically. This view has now gained critical support from the study of multiple disease models discussed herein. Dysfunction of a major astrocyte K(+) channel, Kir4.1, appears as an early pathological event underlying neuronal phenotypes in several neurodevelopmental and neurodegenerative diseases. An expanding list of other astrocyte ion channels, including the calcium-activated ion channel BEST-1, hemichannels, and two-pore domain K(+) channels, all contribute to astrocyte biology and CNS function and underpin new forms of crosstalk between neurons and glia. Once considered merely the glue that holds the brain together, it is now increasingly recognized that astrocytes contribute in several fundamental ways to neuronal function. Emerging new insights and future perspectives of this active research area are highlighted within.
The critical role of astrocyte potassium channels in CNS homeostasis has been reemphasized by recent studies conducted in animal disease models. Emerging evidence also supports the signaling role mediated by astrocyte ion channels such as BEST1, hemichannels, and two-pore channels, which enable astrocytes to interact with neurons and regulate synaptic transmission and plasticity. This minisymposium highlights recent developments and future perspectives of these research areas.
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