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Astrocytes and Microglia-Mediated Immune Response in Maladaptive Plasticity is Differently Modulated by NGF in the Ventral Horn of the Spinal Cord Following Peripheral Nerve Injury

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Abstract

Reactive astrocytes and activated microglia are the key players in several pathophysiologic modifications of the central nervous system. We used the spared nerve injury (SNI) of the sciatic nerve to induce glial maladaptive response in the ventral horn of lumbar spinal cord and examine its role in the remodeling of the tripartite synapse plasticity. Imaging the ventral horn revealed that SNI was associated with both an early microglial and astrocytic activation, assessed, respectively, by analysis of Iba1 and GFAP expression. Microglia, in particular, localized peculiarly surrounding the motor neurons somata. Perineuronal astrocytes, which play a key role in maintaining the homeostasis of neuronal circuitry, underwent a substantial phenotypic change following peripheral axotomy, producing reactive gliosis. The gliosis was associated with the reduction of glial aminoacid transporters (GLT1 and GlyT1) and increase of neuronal glutamate transporter EAAC1. Although the expression of GABAergic neuronal marker GAD65/67 showed no change, glutamate increase, as demonstrated by HPLC analysis, shifted the excitatory/inhibitory balance as showed by the net increase of the glutamate/GABA ratio. Moreover, endogenous NGF levels were altered in SNI animals and not restored by the intrathecal NGF administration. This treatment reverted phenotypic changes associated with reactive astrocytosis, but failed to modify microglia activation. These findings on one hand confirm the correlation between gliopathy and maladaptive plasticity of the spinal synaptic circuitry, on the other hand add new data concerning the complex peculiar behavior of different glial cells in neuronal degenerative processes, defining a special role of microglia in sustaining the inflammatory response.

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Acknowledgments

This work was supported by Grants from the Italian Minister of University and Research (PRIN2007 to M.P. and to A.M.C.); SYSBIONET—Italian ROADMAP ESFRI Infrastructures to L.A., A.M.C., M.P. (fellowship to L.S.); FIRB-ITALBIONET and NEDD to L.A.; Blueprint Pharma s.r.l.; PRIMM, s.r.l.. Research work in authors’ laboratory was funded by Grants from Regione Campania (L.R. N.5 Bando 2003 to M.P.), Regione Campania (Prog. Spec art 12 E.F. 2000 to M.P.), CNR (Neurobiotecnologie 2003 to M.P.), and Associazione Levi-Montalcini (fellowships to G.C.).

Conflict of interest

The authors declare that this article has no conflicts of interest.

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Authors and Affiliations

  1. Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, Via L. Armanni, 5, 80138, Naples, Italy

    Ciro De Luca, Leonilde Savarese, Maria Rosaria Bianco, Giovanni Cirillo & Michele Papa

  2. Laboratory of Neuroscience “R. Levi-Montalcini”, Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy

    Anna Maria Colangelo & Lilia Alberghina

  3. SYSBIO, Centre of Systems Biology, University of Milano-Bicocca, Milan, Italy

    Leonilde Savarese, Anna Maria Colangelo, Lilia Alberghina & Michele Papa

Authors
  1. Ciro De Luca
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  2. Leonilde Savarese
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  3. Anna Maria Colangelo
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  4. Maria Rosaria Bianco
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  5. Giovanni Cirillo
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  6. Lilia Alberghina
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  7. Michele Papa
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Correspondence to Michele Papa.

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De Luca, C., Savarese, L., Colangelo, A.M. et al. Astrocytes and Microglia-Mediated Immune Response in Maladaptive Plasticity is Differently Modulated by NGF in the Ventral Horn of the Spinal Cord Following Peripheral Nerve Injury. Cell Mol Neurobiol 36, 37–46 (2016). https://doi.org/10.1007/s10571-015-0218-2

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