Thyroid hormone increases astrocytic glutamate uptake and protects astrocytes and neurons against glutamate toxicity.
Thyroid hormone (T(3)) regulates the growth and differentiation of rat cerebellar astrocytes. Previously, we have demonstrated that these effects are due, at least in part, to the increased expression of extracellular matrix molecules and growth factors, such as fibroblast growth factor-2. T(3) also modulates neuronal development in an astrocyte-mediated manner. In the mammalian central nervous system, excitatory neurotransmission is mediated mainly by glutamate. However, excessive stimulation of glutamate receptors can lead to excitotoxicity and cell death. Astrocytic glutamate transporters, GLT-1 and GLAST, play an essential role in the clearance of the neuronal-released glutamate from the extracellular space and are essential for maintaining physiological extracellular glutamate levels in the brain. In the present study, we showed that T(3) significantly increased glutamate uptake by cerebellar astrocytes compared with control cultures. Inhibitors of glutamate uptake, such as L-PDC and DL-TBOA, abolished glutamate uptake on control or T(3)-treated astrocytes. T(3) treatment of astrocytes increased both mRNA levels and protein expression of GLAST and GLT-1, although no significant changes on the distribution of these transporters were observed. The gliotoxic effect of glutamate on cultured cerebellar astrocytes was abolished by T(3) treatment of astrocytes. In addition, the neuronal viability against glutamate challenge was enhanced on T(3)-treated astrocytes, showing a putative neuroprotective effect of T(3). In conclusion, our results showed that T(3) regulates extracellular glutamate levels by modulating the astrocytic glutamate transporters. This represents an important mechanism mediated by T(3) on the improvement of astrocytic microenvironment in order to promote neuronal development and neuroprotection.
Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Florianópolis, SC, Brazil.
Cláudia Beatriz Nedel
CB
Mendes-de-Aguiar
Ricardo
R
Alchini
Helena
H
Decker
Marcio
M
Alvarez-Silva
Carla Inês
CI
Tasca
Andréa Gonçalves
AG
Trentin
D027322:Amino Acid Transport System X-AG / Q000096:biosynthesis; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis; D015870:Gene Expression; D018698:Glutamic Acid / Q000378:metabolism*; D007150:Immunohistochemistry; D009474:Neurons / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014284:Triiodothyronine / Q000378:metabolism*
D027322:Amino Acid Transport System X-AG; D027342:Excitatory Amino Acid Transporter 2; D012333:RNA, Messenger; D014284:Triiodothyronine; D018698:Glutamic Acid