Connexin expression by radial glia-like cells is required for neurogenesis in the adult dentate gyrus

Kunze, Anja; Congreso, Marga Rubenecia; Hartmann, Christian; Wallraff-Beck, Anke; Hüttmann, Kerstin; Bedner, Peter; Requardt, Robert P.; Seifert, Gerald; Redecker, Christoph; Willecke, Klaus; Hofmann, Andreas; Pfeifer, Alexander; Theis, Martin; Steinhäuser, Christian

doi:10.1073/pnas.0813160106

Cited by 124 publications

(105 citation statements)

References 39 publications

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“…In addition, we found comparable densities of CA1 pyramidal neurons (NeuN positive) and astrocytes (S100 positive) (Fig. 1B), as recently shown in older Cx30 −/− Cx43 −/− mice (4), although a reduced number of radial glia-like cells and granule neurons was reported in the dentate gyrus (7). Western blot analysis for the pre-and postsynaptic proteins synaptophysin and PSD-95, respectively, revealed no difference between wild type and Cx30 −/− Cx43 −/− mice, suggesting similar total synaptic contacts (Fig.…”

Section: Cx43supporting

confidence: 60%

Astroglial networks scale synaptic activity and plasticity

Pannasch

Vargová

Reingruber

et al. 2011

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

340

338

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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...

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Section: Cx43supporting

confidence: 60%

Astroglial networks scale synaptic activity and plasticity

Pannasch

Vargová

Reingruber

et al. 2011

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

340

338

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“…This hypothesis is supported by neurodevelopmental defects [5], impaired neuronal plasticity [6], accelerated hippocampal spreading depression, enhanced locomotor activity and increased exploratory behaviour [7] in astrocyte-targeted Cx43 knockout mice, as well as altered neurogenesis [8], potassium buffering [9], energy metabolism [10], synaptic activity and plasticity [11], and dysmyelination and vacuolation [12] in Cx43 and Cx30 double knockout mice.…”

Section: Introductionmentioning

confidence: 77%

Astroglial connexin 43 sustains glutamatergic synaptic efficacy

Chever

Pannasch

Ezan

et al. 2014

Phil. Trans. R. Soc. B

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Astrocytes dynamic interactions with neurons play an active role in neurotransmission. The gap junction (GJ) subunits connexins 43 and 30 are strongly expressed in astrocytes and have recently been shown to regulate synaptic activity and plasticity. However, the specific role of connexin 43 in the morphological and electrophysiological properties of astrocytes in situ as well as in synaptic transmission remains unknown. Here, we show that connexin 43, a major determinant of astroglial GJ coupling, regulates astrocyte cell volume, but has no impact on astroglial passive membrane properties. Furthermore, we demonstrate that connexin 43 modulates glutamatergic synaptic activity of hippocampal CA1 pyramidal cells. This regulation involves changes in synaptically released glutamate, with no alteration in neuronal excitability or postsynaptic function. These results reveal connexin 43 as a critical player in neuroglial interactions by supporting synaptic efficacy.

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“…Tracer spread studies performed on Cx30-deficient mice indicated that coupling of astrocytes in the hippocampus predominately depends on Cx43 and only to a minor extent (22%) on Cx30 channels (Gosejacob et al, 2011). Astrocytic gap junction coupling has been supposed to have several functions, including spatial buffering of K 1 ions (Ransom, 1996), trafficking and delivery of energetic metabolites to neurons (Giaume et al, 1997), intercellular propagation of Ca 21 waves (Scemes and Giaume, 2006), volume regulation (Scemes and Spray, 1998), and adult neurogenesis (Kunze et al, 2009). …”

Section: Gap Junctions In Astrocytesmentioning

confidence: 99%

Astrocyte dysfunction in temporal lobe epilepsy: K⁺ channels and gap junction coupling

Steinhäuser

Seifert

Bedner

2012

Glia

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174

172

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Astrocytes are endowed with the machinery to sense and respond to neuronal activity. Recent work has demonstrated that astrocytes play important physiological roles in the CNS, e.g., they synchronize action potential firing, ensure ion homeostasis, transmitter clearance and glucose metabolism, and regulate the vascular tone. Astrocytes are abundantly coupled through gap junctions, which is a prerequisite to redistribute elevated K 1 from sites of excessive neuronal activity to sites of lower extracellular K 1 concentration. Recent studies identified dysfunctional astrocytes as crucial players in epilepsy. Investigation of specimens from patients with pharmacoresistant temporal lobe epilepsy and epilepsy models revealed alterations in expression, localization, and function of astroglial inwardly rectifying K 1 (Kir) channels, particularly Kir4.1, which is suspected to entail impaired K 1 buffering. Gap junctions in astrocytes appear to play a dual role: on the one hand they counteract the generation of hyperactivity by facilitating clearance of elevated extracellular K 1 levels while in contrast, they constitute a pathway for energetic substrate delivery to fuel neuronal (hyper)activity. Recent work suggests that astrocyte dysfunction is causative of the generation or spread of seizure activity. Thus, astrocytes should be considered as promising targets for alternative antiepileptic therapies. V V C 2012 Wiley Periodicals, Inc.

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Connexin expression by radial glia-like cells is required for neurogenesis in the adult dentate gyrus

Cited by 124 publications

References 39 publications

Astroglial networks scale synaptic activity and plasticity

Astroglial networks scale synaptic activity and plasticity

Astroglial connexin 43 sustains glutamatergic synaptic efficacy

Astrocyte dysfunction in temporal lobe epilepsy: K⁺ channels and gap junction coupling

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Connexin expression by radial glia-like cells is required for neurogenesis in the adult dentate gyrus

Cited by 124 publications

References 39 publications

Astroglial networks scale synaptic activity and plasticity

Astroglial networks scale synaptic activity and plasticity

Astroglial connexin 43 sustains glutamatergic synaptic efficacy

Astrocyte dysfunction in temporal lobe epilepsy: K+ channels and gap junction coupling

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Astrocyte dysfunction in temporal lobe epilepsy: K⁺ channels and gap junction coupling