ELEVATED SEIZURE THRESHOLD AND IMPAIRED SPATIAL-LEARNING IN TRANSGENIC MICE WITH PUTRESCINE OVERPRODUCTION IN THE BRAIN

We have studied the role of putrescine by using transgenic mouse lines overexpressing the human ornithine decarboxylase gene in most of thei r tissues. The aberrant expression of the transgene is most strikingly manifested in the brain, leading to an increase of up to 20-fold in p utrescine content. We report that the transgenic mice with grossly ele vated putrescine in all brain regions analysed (cortex, striatum, hipp ocampus and cerebellum) showed a significantly elevated seizure thresh old to chemical and electrical stimuli, and impaired performance in sp atial learning and memory tests. The view that putrescine may be prima rily responsible for these changes was supported by the fact that the concentrations of the major neurotransmitter amino acids, glutamate an d GABA in the brain, were not changed in the transgenic animals, and b y the finding that a further increase in brain putrescine, achieved by inhibition of the catabolism of L-ornithine, appeared to provide addi tional protection against electroshock-induced seizures. These results suggest that the commonly observed increase in ornithine decarboxylas e activity and the massive increase in brain putrescine in connection with neuron damage is a neuroprotective measure rather than a cause of the damage.