Molecular manipulations of extracellular superoxide dismutase: Functional importance for learning

Extracellular superoxide dismutase (EC-SOD) controls the availability of ex tracellular superoxide (O-2(.-)), which is important for a variety of physi ological pathways, including the primary means of inactivating nitric oxide (NO). The role of EC-SOD in neurobehavioral function has been until now un explored. in the current studies, the phenotypic expression of genotypic al terations of EC-SOD production in mice were characterized for spatial learn ing and memory. Dramatic impairments in spatial learning in the win-shift X -arm radial maze were seen in both EC-SOD knockout mice and EC-SOD overexpr essing mice. The EC-SOD overexpressing mice were further characterized as h aving significant deficits in a repeated acquisition task in the radial-arm maze, which permitted the dissociation of long and short-term learning. Lo ng-term learning was significantly impaired by EC-SOD overexpression, where as short-term learning was not significantly affected by EC-SOD overexpress ion. NO systems have been shown to be importantly involved in learning and memory. This may be important in the current studies because EC-SOD has pri mary control over the inactivation of NO. We found that EC-SOD overexpressi ng mice were resistant to the cognitive effects of L-NAME (NG-nitro-L-argin ine methyl ester hydrochloride), an NO synthase inhibitor. Decreased NO cat abolism in these mice may have served to counter the effects of NOS inhibit ion by L-NAME. The current finding that EC-SOD levels that were either high er or lower than controls impaired learning demonstrates that the proper co ntrol of brain extracellular O-2(.-) may be more vital than merely reductio n of brain extracelluar O-2(.-) in maintaining adequate learning function.