Inhibition of Muller cell glutamine synthetase rapidly impairs the retinalresponse to light

It is widely assumed that neurones have sufficient metabolic reserves to al low them to function independently of glial cells for extended periods. The present study investigates the length of time taken before retinal neurone s no longer respond normally to Light after the inhibition of glial enzymes that are involved in the synthesis of precursors of neuronal glutamate. Th e glutamine synthetase inhibitor methionine sulfoximine, when injected intr aocularly in Wister rats, caused a time- and dose-dependent suppression of the scotopic electroretinogram b-wave. At the highest dosage (40 mN) the b- wave was significantly reduced within 2 min of injection. Because the b-wav e is an indicator of neurotransmission in the retina, it is deduced that in hibition of glutamine synthetase rapidly blocks glutamatergic neurotransmis sion. Immunohistochemistry revealed a depletion of neuronal glutamate and a n accumulation of glutamate in Muller glial cells, in a time course that ma tched the b-wave suppression, The b-wave was quickly restored by injection of glutamine (4 mM). The rapid reduction of glutamatergic transmission afte r methionine sulfoximine administration challenges the view that neurones h ave sufficient, reserves to allow them to function independently for extend ed periods; instead, it indicates that glia are essential for the moment-to -moment sustenance of neuronal function. GLIA 30:64-73, 2000. (C) 2000 Wile y-Liss, Inc.