Seifert G, Schilling K, Steinhauser C. Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci 7: 194-206

Department of Experimental Neurobiology, Clinic of Neurosurgery, University of Bonn, Germany.
Nature reviews Neuroscience (Impact Factor: 31.43). 04/2006; 7(3):194-206. DOI: 10.1038/nrn1870
Source: PubMed

ABSTRACT Recent work on glial cell physiology has revealed that glial cells, and astrocytes in particular, are much more actively involved in brain information processing than previously thought. This finding has stimulated the view that the active brain should no longer be regarded solely as a network of neuronal contacts, but instead as a circuit of integrated, interactive neurons and glial cells. Consequently, glial cells could also have as yet unexpected roles in the diseased brain. An improved understanding of astrocyte biology and heterogeneity and the involvement of these cells in pathogenesis offers the potential for developing novel strategies to treat neurological disorders.

31 Reads
  • Source
    • "Further, in amyotrophic lateral sclerosis (ALS), a decreased glutamate transport (Rothstein et al., 1992) as well as a selective loss of EAAT2 was shown (Rothstein et al., 1995). This suggests that a failure of the GGC by astrocytes might be crucial for excitotoxic damage and the subsequent pathogenic process in ALS (Seifert et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Emerging as an important correlate of neurological dysfunction in Multiple Sclerosis (MS), extended focal and diffuse gray matter abnormalities have been found and linked to clinical manifestations such as seizures, fatigue and cognitive dysfunction. To investigate possible underlying mechanisms we analyzed the molecular alterations in histopathological normal appearing cortical gray matter (NAGM) in MS. By performing a differential gene expression analysis of NAGM of control and MS cases we identified reduced transcription of astrocyte specific genes involved in the astrocyte-neuron lactate shuttle (ANLS) and the glutamate-glutamine cycle (GGC). Additional quantitative immunohistochemical analysis demonstrating a CX43 loss in MS NAGM confirmed a crucial involvement of astrocytes and emphasizes their importance in MS pathogenesis. Concurrently, a Toll-like/IL-1β signaling expression signature was detected in MS NAGM, indicating that immune-related signaling might be responsible for the downregulation of ANLS and GGC gene expression in MS NAGM. Indeed, challenging astrocytes with immune stimuli such as IL-1β and LPS reduced their ANLS and GGC gene expression in vitro. The detected upregulation of IL1B in MS NAGM suggests inflammasome priming. For this reason, astrocyte cultures were treated with ATP and ATP/LPS as for inflammasome activation. This treatment led to a reduction of ANLS and GGC gene expression in a comparable manner. To investigate potential sources for ANLS and GGC downregulation in MS NAGM, we first performed an adjuvant-driven stimulation of the peripheral immune system in C57Bl/6 mice in vivo. This led to similar gene expression changes in spinal cord demonstrating that peripheral immune signals might be one source for astrocytic gene expression changes in the brain. IL1B upregulation in MS NAGM itself points to a possible endogenous signaling process leading to ANLS and GGC downregulation. This is supported by our findings that, among others, MS NAGM astrocytes express inflammasome components and that astrocytes are capable to release Il-1β in-vitro. Altogether, our data suggests that immune signaling of immune- and/or central nervous system origin drives alterations in astrocytic ANLS and GGC gene regulation in the MS NAGM. Such a mechanism might underlie cortical brain dysfunctions frequently encountered in MS patients. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 04/2015; 88. DOI:10.1016/j.bbi.2015.04.013 · 5.89 Impact Factor
  • Source
    • "brain capacity of learning and processing ( Han et al . , 2013 ; Krencik et al . , 2011 ; Serio et al . , 2013 ; Witcher et al . , 2010 ) . This is also corroborated by identification of glia dysfunction in several neurological disorders associated with cognitive def - icit such as depression , autism and schizophrenia ( Blackburn et al . , 2009 ; Seifert et al . , 2006 ) . TGF - b1 is a pleiotropic cytokine that plays a wide range of functions both in the healthy nervous system and in brain pathology ( Gomes et al . , 2005 ; Romao et al . , 2008 ; Stipursky et al . , 2012 ; Stipursky and Gomes , 2007 ) . Emerg - ing evidence have been accumulating on how members of TGF - b family , such as TGF - b1 , "
    [Show abstract] [Hide abstract]
    ABSTRACT: The balance between excitatory and inhibitory synaptic inputs is critical for the control of brain function. Astrocytes play important role in the development and maintenance of neuronal circuitry. Whereas astrocytes-derived molecules involved in excitatory synapses are recognized, molecules and molecular mechanisms underlying astrocyte-induced inhibitory synapses remain unknown. Here, we identified transforming growth factor beta 1 (TGF-β1), derived from human and murine astrocytes, as regulator of inhibitory synapse in vitro and in vivo. Conditioned media derived from human and murine astrocytes induce inhibitory synapse formation in cerebral cortex neurons, an event inhibited by pharmacologic and genetic manipulation of the TGF-β pathway. TGF-β1-induction of inhibitory synapse depends on glutamatergic activity and activation of CaM kinase II, which thus induces localization and cluster formation of the synaptic adhesion protein, Neuroligin 2, in inhibitory postsynaptic terminals. Additionally, intraventricular injection of TGF-β1 enhanced inhibitory synapse number in the cerebral cortex. Our results identify TGF-β1/CaMKII pathway as a novel molecular mechanism underlying astrocyte control of inhibitory synapse formation. We propose here that the balance between excitatory and inhibitory inputs might be provided by astrocyte signals, at least partly achieved via TGF-β1 downstream pathways. Our work contributes to the understanding of the GABAergic synapse formation and may be of relevance to further the current knowledge on the mechanisms underlying the development of various neurological disorders, which commonly involve impairment of inhibitory synapse transmission. GLIA 2014
    Glia 12/2014; 62(12). DOI:10.1002/glia.22713 · 6.03 Impact Factor
  • Source
    • "For example, astrocytes regulate glutamatergic neurotransmission and prevent glutamate excitotoxicity by removing excess glutamate from the extracellular synaptic space through glutamate transporters [24]. Astrocyte dysfunction has been implicated in a variety of neurological diseases [25]. Based on this, it is necessary to investigate effects of DMSO on astrocytes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dimethyl sulfoxide (DMSO) is a polar organic solvent that is used to dissolve neuroprotective or neurotoxic agents in neuroscience research. However, DMSO itself also has pharmacological and pathological effects on the nervous system. Astrocytes play a central role in maintaining brain homeostasis, but the effect and mechanism of DMSO on astrocytes has not been studied. The present study showed that exposure of astrocyte cultures to 1% DMSO for 24 h did not significantly affect cell survival, but decreased cell viability and glial glutamate transporter expression, and caused mitochondrial swelling, membrane potential impairment and reactive oxygen species production, and subsequent cytochrome c release and caspase-3 activation. DMSO at concentrations of 5% significantly inhibited cell variability and promoted apoptosis of astrocytes, accompanied with more severe mitochondrial damage. These results suggest that mitochondrial impairment is a primary event in DMSO-induced astrocyte toxicity. The potential cytotoxic effects on astrocytes need to be carefully considered during investigating neuroprotective or neurotoxic effects of hydrophobic agents dissolved by DMSO.
    PLoS ONE 09/2014; 9(9):e107447. DOI:10.1371/journal.pone.0107447 · 3.23 Impact Factor
Show more