Reactive astrocytosis-induced perturbation of synaptic homeostasis is restored by nerve growth factor.
Reactive gliosis has been implicated in both inflammatory and neurodegenerative diseases. However, mechanisms by which astrocytic activation affects synaptic efficacy have been poorly elucidated. We have used the spared nerve injury (SNI) of the sciatic nerve to induce reactive astrocytosis in the lumbar spinal cord and investigate its potential role in disrupting the neuro-glial circuitry. Analysis of spinal cord sections revealed that SNI was associated with an increase of microglial (Iba1) and astrocytic (GFAP) markers. These changes, indicative of reactive gliosis, were paralleled by (i) a decrease of glial amino acid transporters (GLT1 and GlyT1) and increased levels of (ii) neuronal glutamate transporter EAAC1, (iii) neuronal vesicular GABA transporter (vGAT) and (iv) the GABAergic neuron marker GAD65/67. Besides the increase of Glutamate/GABA ratio, indicative of the perturbation of synaptic circuitry homeostasis, the boost of glutamate also compromised glial function in neuroprotection by up-regulating the xCT subunit of the glutamate-cystine antiport system and reducing glutathione (GSH) production. Finally, this study also shows that all these structural changes were linked to an alteration of endogenous NGF metabolism, as demonstrated by the decrease of endogenous NGF expression levels and increased activity of the NGF-degrading metalloproteinases. All the changes displayed by SNI-animals were reversed by a 7-days i.t. administration of NGF or GM6001, a generic metalloproteinase inhibitor, as compared to vehicle (ACSF)-treated animals. All together, these data strongly support the correlation between reactive astrogliosis and mechanisms underlying the perturbation of the synaptic circuitry in the SNI model of peripheral nerve injury, and the essential role of NGF in restoring both synaptic homeostasis and the neuroprotective function of glia.
Laboratorio di Morfologia delle Reti Neuronali, Dipartimento di Medicina Pubblica Clinica e Preventiva, Seconda Università di Napoli, 80138 Naples, Italy.
Giovanni
G
Cirillo
Maria Rosaria
MR
Bianco
Anna Maria
AM
Colangelo
Carlo
C
Cavaliere
De Luca
de L
Daniele
Laura
L
Zaccaro
Lilia
L
Alberghina
Michele
M
Papa
D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D005911:Gliosis / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D008297:Male; D020932:Nerve Growth Factor / Q000502:physiology / Q000627:therapeutic use*; D009434:Neural Pathways / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D013569:Synapses / Q000502:physiology*
D020932:Nerve Growth Factor