INHIBITION OF GLUTAMINE-SYNTHETASE ACTIVITY PREVENTS MEMORY CONSOLIDATION

Methionine sulfoximine, a specific inhibitor of the exclusively glial enzyme glutamine synthetase, was shown, at a concentration of 3.5-4.5 mM, to prevent consolidation of memory for a passive avoidance task in day-old chicks. Provided the drug was administered 5-20 min before th e learning task, significant retention loss was observed from the norm al time of onset of the second of three postulated stages in the memor y formation sequence but the drug had to be administered considerably earlier. The amnestic effect of methionine sulfoximine was successfull y counteracted by L-glutamine (10 mM) and monosodium glutamate (4 mM), and also by a cocktail of alpha-ketoglutarate (5 mM) and alanine (5 m M). This effect of methionine sulfoximine is attributed to its blockad e of the production of glutamine via the glutamate-glutamine cycle, le ading to a reduced capacity of neurons to replenish their transmitter glutamate.