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Selective induction of astrocytic gliosis generates deficits in neuronal inhibition

Nature Neuroscience volume 13, pages 584–591 (2010)Cite this article

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Abstract

Reactive astrocytosis develops in many neurologic diseases, including epilepsy. Astrocytotic contributions to pathophysiology are poorly understood. Studies examining this are confounded by comorbidities accompanying reactive astrocytosis. We found that high-titer transduction of astrocytes with enhanced green fluorescent protein (eGFP) via adeno-associated virus induced reactive astrocytosis without altering the intrinsic properties or anatomy of neighboring neurons. We examined the consequences of selective astrocytosis induction on synaptic transmission in mouse CA1 pyramidal neurons. Neurons near eGFP-labeled reactive astrocytes had reduced inhibitory, but not excitatory, synaptic currents. This inhibitory postsynaptic current (IPSC) erosion resulted from a failure of the astrocytic glutamate-glutamine cycle. Reactive astrocytes downregulated expression of glutamine synthetase. Blockade of this enzyme normally induces rapid synaptic GABA depletion. In astrocytotic regions, residual inhibition lost sensitivity to glutamine synthetase blockade, whereas exogenous glutamine administration enhanced IPSCs. Astrocytosis-mediated deficits in inhibition triggered glutamine-reversible hyperexcitability in hippocampal circuits. Thus, reactive astrocytosis could generate local synaptic perturbations, leading to broader functional deficits associated with neurologic disease.

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Figure 1: Astrocyte-specific eGFP expression.
Figure 2: AAV2/5–Gfa104-eGFP induces a titer-dependent reactivity of astrocytes.
Figure 3: Inhibitory neurotransmission is impaired in CA1 pyramidal cells proximal to reactive astrocytes.
Figure 4: Preserved excitatory neurotransmission in CA1 pyramidal neurons proximal to reactive astrocytes.
Figure 5: Glutamate-glutamine cycle deficits reduce the concentration of vesicular GABA.
Figure 6: Reactive gliosis is associated with network hyperexcitability.

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Acknowledgements

This work was supported by US National Institutes of Health grants P01 NS054900 and P20 MH071705 to D.A.C., P01NS054900, R01NS054770 and R01NS037585 to P.G.H., R01NS040978 to D.J.W. and by an Epilepsy Foundation Research Fellowship to P.I.O.

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Author notes

  1. Pavel I Ortinski and Jinghui Dong: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Pavel I Ortinski, Cuiyong Yue, Hajime Takano & Douglas A Coulter

  2. Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts, USA

    Jinghui Dong, Alison Mungenast & Philip G Haydon

  3. Department of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Deborah J Watson

  4. Departments of Pediatrics and Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Douglas A Coulter

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  1. Pavel I Ortinski
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Contributions

P.I.O. and J.D. conducted and analyzed all of the experiments. A.M. assisted with viral vector production. C.Y. contributed to VSD data collection and analysis. H.T. assisted with confocal and multiphoton microscope data acquisition and processing. D.J.W. contributed to initial generation of the AAV-injected mice. P.I.O. and D.A.C. wrote the manuscript with help from P.G.H. and J.D. D.A.C. and P.G.H. designed the experiments with P.I.O. and J.D. and supervised the project.

Corresponding author

Correspondence to Douglas A Coulter.

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The authors declare no competing financial interests.

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Ortinski, P., Dong, J., Mungenast, A. et al. Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat Neurosci 13, 584–591 (2010). https://doi.org/10.1038/nn.2535

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