OXTR-mediated signaling in astrocytes contributes to anxiolysis.

Astrocytes are an indispensable part of signal processing within the mammalian brain. Thus, the mode of action of a neuropeptide such as oxytocin (OXT) can only be fully understood considering this integral part of the CNS. Here, we show that OXT regulates astrocytic gene expression, intracellular signaling and specific proteins both in vitro and in vivo.

Calcium wave dynamics in the embryonic mouse gut mesenchyme: impact on smooth muscle differentiation.

Intestinal smooth muscle differentiation is a complex physico-biological process involving several different pathways. Here, we investigate the properties of Ca waves in the developing intestinal mesenchyme using GCamp6f expressing mouse embryos and investigate their relationship with smooth muscle differentiation. We find that Ca waves are absent in the pre-differentiation mesenchyme and start propagating immediately following α-SMA expression.

Retinal damage promotes mitochondrial transfer in the visual system of a mouse model of Leber hereditary optic neuropathy.

Lenadogene nolparvovec is a gene therapy which has been developed to treat Leber hereditary optic neuropathy (LHON) caused by a point mutation in the mitochondrial NADH dehydrogenase 4 (ND4) gene. Clinical trials have demonstrated a significant improvement of visual acuity up to 5 years after treatment by lenadogene nolparvovec but, surprisingly, unilateral treatment resulted in bilateral improvement of vision. This contralateral effect - similarly observed with other gene therapy products in development for MT-ND4-LHON - is supported by the migration of viral vector genomes and their transcripts to the contralateral eye, as reported in animals, and post-mortem samples from two patients.

Astroglial networks control visual responses of superior collicular neurons and sensory-motor behavior.

Astroglial networks closely interact with neuronal populations, but their functional contribution to neuronal representation of sensory information remains unexplored. The superior colliculus (SC) integrates multi-sensory information by generating distinct spatial patterns of neuronal functional responses to specific sensory stimulation. Here, we report that astrocytes from the mouse SC form extensive networks in the retinorecipient layer compared to visual cortex.

Connexin 30 locally controls actin cytoskeleton and mechanical remodeling in motile astrocytes.

During brain maturation, astrocytes establish complex morphologies unveiling intense structural plasticity. Connexin 30 (Cx30), a gap-junction channel-forming protein expressed postnatally, dynamically regulates during development astrocyte morphological properties by controlling ramification and extension of fine processes. However, the underlying mechanisms remain unexplored.

Astroglial gap junctions strengthen hippocampal network activity by sustaining afterhyperpolarization via KCNQ channels.

Throughout the brain, astrocytes form networks mediated by gap junction channels that promote the activity of neuronal ensembles. Although their inputs on neuronal information processing are well established, how molecular gap junction channels shape neuronal network patterns remains unclear. Here, using astroglial connexin-deficient mice, in which astrocytes are disconnected and neuronal bursting patterns are abnormal, we show that astrocyte networks strengthen bursting activity via dynamic regulation of extracellular potassium levels, independently of glutamate homeostasis or metabolic support.

Astroglial Kir4.1 potassium channel deficit drives neuronal hyperexcitability and behavioral defects in Fragile X syndrome mouse model.

Fragile X syndrome (FXS) is an inherited form of intellectual disability caused by the loss of the mRNA-binding fragile X mental retardation protein (FMRP). FXS is characterized by neuronal hyperexcitability and behavioral defects, however the mechanisms underlying these critical dysfunctions remain unclear. Here, using male Fmr1 knockout mouse model of FXS, we identify abnormal extracellular potassium homeostasis, along with impaired potassium channel Kir4.

Inhibiting astrocyte connexin-43 hemichannels blocks radiation-induced vesicular VEGF-A release and blood-brain barrier dysfunction.

Therapeutic brain irradiation with ionizing radiation exerts multiple side effects including barrier leakage that disturbs glial-neuronal functioning and may affect cognition. Astrocytes contribute to barrier leakage by endfeet release of various vasoactive substances acting on capillary endothelial cells forming the barrier. Here, we investigated X-ray effects on astrocytic vesicular transport in mice and determined whether interfering with astrocyte connexins affects radiation-induced barrier leakage.

Diversity of dynamic voltage patterns in neuronal dendrites revealed by nanopipette electrophysiology.

Dendrites and dendritic spines are the essential cellular compartments in neuronal communication, conveying information through transient voltage signals. Our understanding of these compartmentalized voltage dynamics in fine, distal neuronal dendrites remains poor due to the difficulties inherent to accessing and stably recording from such small, nanoscale cellular compartments for a sustained time. To overcome these challenges, we use nanopipettes that permit long and stable recordings directly from fine neuronal dendrites.

Epigenetic changes in astrocytes make sense.

Serotonin induces gene expression changes in astrocytes to regulate olfactory behavior.

Astroglial Connexin 43 Regulates Synaptic Vesicle Release at Hippocampal Synapses.

Connexin 43, an astroglial gap junction protein, is enriched in perisynaptic astroglial processes and plays major roles in synaptic transmission. We have previously found that astroglial Cx43 controls synaptic glutamate levels and allows for activity-dependent glutamine release to sustain physiological synaptic transmissions and cognitiogns. However, whether Cx43 is important for the release of synaptic vesicles, which is a critical component of synaptic efficacy, remains unanswered.

The ribosome-associated protein RACK1 represses Kir4.1 translation in astrocytes and influences neuronal activity.

The regulation of translation in astrocytes, the main glial cells in the brain, remains poorly characterized. We developed a high-throughput proteomics screen for polysome-associated proteins in astrocytes and focused on ribosomal protein receptor of activated protein C kinase 1 (RACK1), a critical factor in translational regulation. In astrocyte somata and perisynaptic astrocytic processes (PAPs), RACK1 preferentially binds to a number of mRNAs, including Kcnj10, encoding the inward-rectifying potassium (K) channel Kir4.

Upregulation of astroglial connexin 30 impairs hippocampal synaptic activity and recognition memory.

Astrocytes crucially contribute to synaptic physiology and information processing. One of their key characteristics is to express high levels of connexins (Cxs), the gap junction-forming protein. Among them, Cx30 displays specific properties since it is postnatally expressed and dynamically upregulated by neuronal activity and modulates cognitive processes by shaping synaptic and network activities, as recently shown in knockout mice.

Activation of the PI3K/AKT/mTOR Pathway in Cajal-Retzius Cells Leads to Their Survival and Increases Susceptibility to Kainate-Induced Seizures.

Cajal-Retzius cells (CRs) are a class of transient neurons in the mammalian cortex that play a critical role in cortical development. Neocortical CRs undergo almost complete elimination in the first two postnatal weeks in rodents and the persistence of CRs during postnatal life has been detected in pathological conditions related to epilepsy. However, it is unclear whether their persistence is a cause or consequence of these diseases.

Aberrant survival of hippocampal Cajal-Retzius cells leads to memory deficits, gamma rhythmopathies and susceptibility to seizures in adult mice.

Cajal-Retzius cells (CRs) are transient neurons, disappearing almost completely in the postnatal neocortex by programmed cell death (PCD), with a percentage surviving up to adulthood in the hippocampus. Here, we evaluate CR's role in the establishment of adult neuronal and cognitive function using a mouse model preventing Bax-dependent PCD. CRs abnormal survival resulted in impairment of hippocampus-dependent memory, associated in vivo with attenuated theta oscillations and enhanced gamma activity in the dorsal CA1.

Prostaglandin D Controls Local Blood Flow and Sleep-Promoting Neurons in the VLPO via Astrocyte-Derived Adenosine.

Prostaglandin D (PGD) is one of the most potent endogenous sleep-promoting molecules. However, the cellular and molecular mechanisms of the PGD-induced activation of sleep-promoting neurons in the ventrolateral preoptic nucleus (VLPO), the major nonrapid eye movement (NREM)-sleep center, still remains unclear. We here show that PGD receptors (DP) are not only expressed in the leptomeninges but also in astrocytes from the VLPO.

Astrocytic Kir4.1 channels regulate locomotion by orchestrating neuronal rhythmicity in the spinal network.

Neuronal rhythmogenesis in the spinal cord is correlated with variations in extracellular K levels ([K ] ). Astrocytes play important role in [K ] homeostasis and compute neuronal information. Yet it is unclear how neuronal oscillations are regulated by astrocytic K homeostasis.

Pannexin 1 activity in astroglia sets hippocampal neuronal network patterns.

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.

Astroglial Connexins Inactivation Increases Relapse of Depressive-like Phenotype after Antidepressant Withdrawal.

Studies suggest that astrocytic connexins (Cx) have an important role in the regulation of high brain functions through their ability to establish fine-tuned communication with neurons within the tripartite synapse. In light of these properties, growing evidence suggests a role of Cx in psychiatric disorders such as major depression but also in the therapeutic activity of antidepressant drugs. However, the real impact of Cx on treatment response and the underlying neurobiological mechanisms remain yet to be clarified.

Targeting gliovascular connexins prevents inflammatory blood-brain barrier leakage and astrogliosis.

The blood-brain barrier is formed by capillary endothelial cells expressing connexin 37 (Cx37), Cx40, and Cx43 and is joined by closely apposed astrocytes expressing Cx43 and Cx30. We investigated whether connexin-targeting peptides could limit barrier leakage triggered by LPS-induced systemic inflammation in mice. Intraperitoneal LPS administration increased endothelial and astrocytic Cx43 expression; elevated TNF-α, IL-1β, IFN-γ, and IL-6 in plasma and IL-6 in the brain; and induced barrier leakage recorded over 24 hours.

Myotonic dystrophy RNA toxicity alters morphology, adhesion and migration of mouse and human astrocytes.

Brain dysfunction in myotonic dystrophy type 1 (DM1), the prototype of toxic RNA disorders, has been mainly attributed to neuronal RNA misprocessing, while little attention has been given to non-neuronal brain cells. Here, using a transgenic mouse model of DM1 that expresses mutant RNA in various brain cell types (neurons, astroglia, and oligodendroglia), we demonstrate that astrocytes exhibit impaired ramification and polarization in vivo and defects in adhesion, spreading, and migration. RNA-dependent toxicity and phenotypes are also found in human transfected glial cells.

Correction: Fast calcium transients in dendritic spines driven by extreme statistics.

[This corrects the article DOI: 10.1371/journal.pbio.

Hippocampal Excitatory Synaptic Transmission and Plasticity Are Differentially Altered during Postnatal Development by Loss of the X-Linked Intellectual Disability Protein Oligophrenin-1.

Oligophrenin-1 (OPHN1) is a Rho-GTPase-activating protein (RhoGAP), whose mutations are associated with X-linked intellectual disability (XLID). OPHN1 is enriched at the synapse in both pre- and postsynaptic compartments, where it regulates the RhoA/ROCK/MLC2 signaling pathway, playing a critical role in cytoskeleton remodeling and vesicle recycling. knockout (KO) adult mice display some behavioral deficits in multiple tasks, reminiscent of some symptoms in the human pathology.