Inhibition of Müller cell glutamine synthetase rapidly impairs the retinal response to light.
It is widely assumed that neurones have sufficient metabolic reserves to allow them to function independently of glial cells for extended periods. The present study investigates the length of time taken before retinal neurones no longer respond normally to light after the inhibition of glial enzymes that are involved in the synthesis of precursors of neuronal glutamate. The glutamine synthetase inhibitor methionine sulfoximine, when injected intraocularly in Wistar rats, caused a time- and dose-dependent suppression of the scotopic electroretinogram b-wave. At the highest dosage (40 mM) the b-wave was significantly reduced within 2 min of injection. Because the b-wave is an indicator of neurotransmission in the retina, it is deduced that inhibition of glutamine synthetase rapidly blocks glutamatergic neurotransmission. Immunohistochemistry revealed a depletion of neuronal glutamate and an accumulation of glutamate in Müller glial cells, in a time course that matched the b-wave suppression. The b-wave was quickly restored by injection of glutamine (4 mM). The rapid reduction of glutamatergic transmission after methionine sulfoximine administration challenges the view that neurones have sufficient reserves to allow them to function independently for extended periods; instead, it indicates that glia are essential for the moment-to-moment sustenance of neuronal function.
Barnett
N L
NL
Vision, Touch & Hearing Research Centre, The University of Queensland, Brisbane, Australia. N.Barnett@vthrc.uq.edu.au
Pow
D V
DV
Robinson
S R
SR
D000704:Analysis of Variance; D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D004596:Electroretinography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors*; D005973:Glutamine / Q000378:metabolism; D007150:Immunohistochemistry; D008027:Light; D008717:Methionine Sulfoximine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000528:radiation effects*; D013997:Time Factors
D004791:Enzyme Inhibitors; D005973:Glutamine; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005974:Glutamate-Ammonia Ligase