A full list of affiliations appears at the end of the paper. 'N euroglia' or 'glia' are collective terms describing cells of neuroepithelial (oligodendrocytes, astrocytes, oligodendrocyte progenitor cells, ependymal cells), neural crest (peripheral glia), and myeloid (microglia) origin. Changes in neuroglia associated with diseases of the CNS have been noted, characterized, and conceptualized from the very dawn of neuroglial research. Rudolf Virchow, in a lecture to students and medical doctors in 1858, stressed that 'this very interstitial tissue [that is, neuroglia] of the brain and spinal marrow is one of the most frequent seats of morbid change... ' 1. Changes in the shape, size, or number of glial cells in various pathological contexts have been frequently described by prominent neuroanatomists 2. In particular, hypertrophy of astrocytes was recognized very early as an almost universal sign of CNS pathology: 'the protoplasmic glia elements [that is, astrocytes] are really the elements which exhibit a morbid hypertrophy in pathological conditions' 3. Neuroglial proliferation was thought to accompany CNS lesions, leading to early suggestions that proliferating glia fully replaced damaged neuronal elements 4. Thus, a historical consensus was formed that a change in 'the appearance of neuroglia serves as a delicate indicator of the action of noxious influences upon the central nervous system, ' and the concept of 'reactionary change or gliosis' was accepted 5. While the origin of 'gliosis' is unclear (glia + osis in Greek means 'glial condition or process'; in Latin the suffix-osis acquired the additional meaning of 'disease'; hence 'astrogliosis'

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.

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.

Astrocytes dynamically interact with neurons to regulate synaptic transmission. Although the gap junction proteins connexin 30 (Cx30) and connexin 43 (Cx43) mediate the extensive network organization of astrocytes, their role in synaptic physiology is unknown. Here we show, by inactivating Cx30 and Cx43 genes, that astroglial networks tone down hippocampal synaptic transmission in CA1 pyramidal neurons. Gap junctional networking facilitates extracellular glutamate and potassium removal during synaptic activity through modulation of astroglial clearance rate and extracellular space volume. This regulation limits neuronal excitability, release probability, and insertion of postsynaptic AMPA receptors, silencing synapses. By controlling synaptic strength, connexins play an important role in synaptic plasticity. Altogether, these results establish connexins as critical proteins for extracellular homeostasis, important for the formation of functional synapses. hippocampus | neuroglial interactionsA strocytes, elements of the tripartite synapse, integrate and modulate neuronal excitability, synaptic transmission, and plasticity (1). Up to now the involvement of astrocytes in central functions has mostly been considered to result from the activity of individual astrocytes. However, a typical feature of astrocytes is their network organization provided by numerous gap junction channels formed by two main connexin (Cx) subunits, Cx43, present from embryonic to adult stages, and Cx30, expressed later in development (2). Gap junction channels consist of two hemichannels, each composed of six Cx subunits that align between adjacent cells to form intercellular channels. They mediate direct intercellular communication involving exchange of ions (electrical coupling) and small signaling molecules (biochemical coupling), with a molecular weight up to 1.5 kDa. Intercellular trafficking and redistribution of neuroactive substances, such as ions and neurotransmitters, through gap junction channels during neuronal activity suggest that astroglial network communication plays a role in neuroglial interactions and neurotransmission. This hypothesis is supported by altered behavior in Cx30 and astrocyte-targeted Cx43 knockout mice (3), as well as by impairment in sensorimotor and spatial memory tasks in Cx43 and Cx30 double-knockout mice (4). In addition, these channels have recently been shown to be important for neuronal activity during pathological conditions, such as hypoglycemia (5) and epilepsy (6), by mediating nutrient transport and spatial potassium buffering, respectively. However, their role in basal neurotransmission and synaptic plasticity is unknown. Thus, the aim of this work was to determine whether and how the connectivity of astroglial networks contributes to basal synaptic transmission and plasticity. We here demonstrate that mice deficient for both astroglial Cx30 and Cx43 have increased hippocampal synaptic transmission and impaired long-term synaptic plasticity. These effects are due to decreased astroglial glutam...

Synaptic plasticity involves activity-dependent trafficking of AMPA-type glutamate receptors. Numerous cytoplasmic scaffolding proteins are postulated to control AMPA receptor trafficking, but the detailed mechanisms remain unclear. Here, we show that the transmembrane AMPA receptor regulatory protein (TARP) gamma-8, which is preferentially expressed in the mouse hippocampus, is important for AMPA receptor protein levels and extrasynaptic surface expression. By controlling the number of AMPA receptors, gamma-8 is also important in long-term potentiation, but not long-term depression. This study establishes gamma-8 as a critical protein for basal AMPA receptor expression and localization at extrasynaptic sites in the hippocampus and raises the possibility that TARP-dependent control of AMPA receptors during synapse development and plasticity may be widespread.

Gap junctions are widely expressed in the various cell types of the central nervous system. These specialized membrane intercellular junctions provide the morphological support for direct electrical and biochemical communication between adjacent cells. This intercellular coupling is controlled by neurotransmitters and other endogenous compounds produced and released in basal as well as in pathological situations. Changes in the expression and the function of connexins are associated with number of brain pathologies and lesions suggesting that they could contribute to the expansion of brain damages. The purpose of this review is to summarize data presently available concerning gap junctions and the expression and function of connexins in different cell types of the central nervous system and to present their physiopathological relevance in three major brain dysfunctions: inflammation, epilepsy and ischemia.

Astrocytes play active roles in brain physiology by dynamic interactions with neurons. Connexin 30, one of the two main astroglial gap-junction subunits, is thought to be involved in behavioral and basic cognitive processes. However, the underlying cellular and molecular mechanisms are unknown. We show here in mice that connexin 30 controls hippocampal excitatory synaptic transmission through modulation of astroglial glutamate transport, which directly alters synaptic glutamate levels. Unexpectedly, we found that connexin 30 regulated cell adhesion and migration and that connexin 30 modulation of glutamate transport, occurring independently of its channel function, was mediated by morphological changes controlling insertion of astroglial processes into synaptic clefts. By setting excitatory synaptic strength, connexin 30 plays an important role in long-term synaptic plasticity and in hippocampus-based contextual memory. Taken together, these results establish connexin 30 as a critical regulator of synaptic strength by controlling the synaptic location of astroglial processes.

Data collected on astrocytes’ physiology in the rodent have placed them as key regulators of synaptic, neuronal, network, and cognitive functions. While these findings proved highly valuable for our awareness and appreciation of non-neuronal cell significance in brain physiology, early structural and phylogenic investigations of human astrocytes hinted at potentially different astrocytic properties. This idea sparked interest to replicate rodent-based studies on human samples, which have revealed an analogous but enhanced involvement of astrocytes in neuronal function of the human brain. Such evidence pointed to a central role of human astrocytes in sustaining more complex information processing. Here, we review the current state of our knowledge of human astrocytes regarding their structure, gene profile, and functions, highlighting the differences with rodent astrocytes. This recent insight is essential for assessment of the relevance of findings using animal models and for comprehending the functional significance of species-specific properties of astrocytes. Moreover, since dysfunctional astrocytes have been described in many brain disorders, a more thorough understanding of human-specific astrocytic properties is crucial for better-adapted translational applications.