Impairment of long-term potentiation and associative memory in mice that overexpress extracellular superoxide dismutase

Reactive oxygen species, including superoxide, generally are considered neu rotoxic molecules whose effects can be alleviated by antioxidants. Differen t from this view, we show that scavenging of superoxide with an antioxidant enzyme is associated with deficits in hippocampal long-term potentiation ( LTP), a putative neural substrate of memory, and hippocampal-mediated memor y function. Using transgenic mice that overexpress extracellular superoxide dismutase (EC-SOD), a superoxide scavenger, we found that LTP was impaired in hippocampal area CA1 despite normal LTP in area CA3. The LTP impairment in area CA1 could be reversed by inhibition of EC-SOD. In addition, we fou nd that EC-SOD transgenic mice exhibited impaired long-term memory of fear conditioning to contextual cues despite exhibiting normal short-term memory of the conditioning experience. These findings strongly suggest that super oxide, rather than being considered exclusively a neurotoxic molecule, shou ld also be considered a signaling molecule necessary for normal neuronal fu nction.