Activated astrocytes in areas of kainate-induced neuronal injury upregulate the expression of the metabotropic glutamate receptors 2/3 and 5

Abstract

All forms of brain injury induce activation of astrocytes, although different types of injury induce different astrocytic responses. Activated astrocytes are characterised by hypertrophy, proliferation and increased expression of glial fibrillary acidic protein (GFAP). However, neither the process by which astrocytes become reactive nor the consequences are well understood. Recently, the application of specific growth factors to primary astrocytic cultures was shown to regulate dramatically the level of expression of the metabotropic glutamate receptors (mGluR) 5 and 3. In the present study, we have used an intracerebroventricular injection of a subconvulsive dose of kainic acid to produce a lesion of CA3a pyramidal neurones in the mouse hippocampus and to investigate whether mGluR expression was altered in reactive astrocytes in vivo. Immunohistochemical analysis showed strong mGluR5 and mGluR2/3 immunoreactivity in glial cells within the area of neuronal loss possessing the morphological feature of activated astrocytes. Double labelling with GFAP confirmed the expression of mGluRs by reactive astrocytes. The mechanical injury produced by the needle insertion in the cerebral cortex also produced enhanced expression of mGluR5 and mGluR2/3 in activated astrocytes proximal to the area of neuronal injury. Our finding of an increased mGluR expression in reactive astrocytes in vivo suggests that transcriptional regulation by specific growth factors on mGluRs is a phenomenon extendible to specific circumstances in vivo and not limited to in vitro models. Identification of the mechanisms of this adaptive plasticity will be central in the understanding of the events leading to neuronal survival and/or death.

Role of γ-aminobutyric acid B (GABAB) receptors in the regulation of kainic acid-induced cell death in mouse hippocampus

“…Reactive astrocytes were detected in mice i.c.v. administered with KA (Ferraguti et al, 2001;Cho et al, 2002). Our data showed the appearance of reactive astrocytes in the CA3 region of hippocampus at 1 day after i.c.v.…”

“…KA administration (Roe et al, 1998;Matsuoka et al, 1999). KA, administered i.c.v., induced the lesion of CA3 pyramidal neurons in mice (Ferraguti et al, 2001;Lee et al, 2002;Lee et al, 2003). The phosphorylated extracellular signal-regulated kinase (p-ERK) is increased by systemic administration of KA in the rat hippocampus (Mielke et al, 1999;Jeon et al, 2000).…”

“…Reactive astrocytes are detected in mice i.c.v. administered KA (Ferraguti et al, 2001;Cho et al, 2002). The activation of microglia can be detected using an activated microglial marker, complement receptor type 3 (OX-42).…”

Agonists and Antagonists of Metabotropic Glutamate Receptors: Anticonvulsants and Antiepileptogenic Agents?

“…In our study, no obvious increase of mGluR4 protein was observed in the hippocampus from patients with the same subtype of epilepsy [66]. Similar to the kindling model, mGluR5 and mGluR2/3 were also increased in astrocytes in kainate-induced epileptic seizures, [25,75]. However, in the pilocarpine model, no upregulation of mGluR2/3 and mGluR5 in astrocytes was demonstrated [64].…”

Tf-lipoplex-mediated NGF gene transfer to the CNS: neuronal protection and recovery in an excitotoxic model of brain injury

“…Kainic acid is known to induce neuronal cell death in animal models, mimicking the injuries observed in neurodegenerative disorders such as Alzheimer's and Huntington's diseases, and in acute neurological lesions such as ischaemia, hypoglycaemia and trauma. [30][31][32][33] …”