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Inhibition of glutamine synthetase activity prevents memory consolidation
M E Gibbs1, B S O'Dowd, L Hertz
1Department of Psychology, Monash University, Clayton, Vic, Australia.
Abstract:
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 the learning task, significant retention loss was observed from the normal time of onset of the second of three postulated stages in the memory formation sequence but the drug had to be administered considerably earlier. The amnestic effect of methionine sulfoximine was successfully counteracted by L-glutamine (10 mM) and monosodium glutamate (4 mM), and also by a cocktail of alpha-ketoglutarate (5 mM) and alanine (5 mM). This effect of methionine sulfoximine is attributed to its blockade of the production of glutamine via the glutamate-glutamine cycle, leading to a reduced capacity of neurons to replenish their transmitter glutamate.
Insights
Methionine sulfoximine inhibits memory consolidation in chicks by blocking glutamine synthesis. This memory loss was reversed by L-glutamine or glutamate, suggesting a role for the glutamate-glutamine cycle in memory formation.
Area of Science:
- Neuroscience
- Biochemistry
- Animal Behavior
Background:
- Glutamine synthetase is a key enzyme in glial cells, responsible for synthesizing glutamine.
- The glutamate-glutamine cycle plays a crucial role in neurotransmission and neuronal function.
- Memory consolidation is a complex process involving molecular and cellular changes in the brain.
Purpose of the Study:
- To investigate the role of glutamine synthetase inhibition by methionine sulfoximine in memory consolidation.
- To determine the effects of methionine sulfoximine on passive avoidance learning in young chicks.
- To explore potential counteracting agents for the amnestic effects of methionine sulfoximine.
Main Methods:
- Administering methionine sulfoximine, a glutamine synthetase inhibitor, to day-old chicks before a passive avoidance learning task.
- Assessing memory retention at different time points after drug administration and learning.
- Evaluating the effects of L-glutamine, monosodium glutamate, alpha-ketoglutarate, and alanine on memory retention in chicks treated with methionine sulfoximine.
Main Results:
- Methionine sulfoximine (3.5-4.5 mM) significantly impaired memory consolidation for the passive avoidance task when administered 5-20 minutes prior to learning.
- Earlier administration of methionine sulfoximine was required for a more pronounced amnestic effect.
- The memory-impairing effects of methionine sulfoximine were successfully reversed by L-glutamine (10 mM) and monosodium glutamate (4 mM), as well as a combination of alpha-ketoglutarate (5 mM) and alanine (5 mM).
Conclusions:
- Inhibition of glutamine synthetase by methionine sulfoximine disrupts memory consolidation in young chicks.
- The findings suggest that the glutamate-glutamine cycle and subsequent replenishment of neuronal glutamate are critical for memory formation.
- Restoring glutamine or glutamate levels can counteract the amnestic effects, highlighting the importance of this metabolic pathway in learning and memory.