Learning, memory and long-term potentiation are altered in Nedd4 heterozygous mice

• Nedd4 expression is abundant in the hippocampus.
• Nedd4 heterozygous mice show significant decrease in long-term spatial learning and memory.
• A significant decrease in long-term potentiation (LTP) was observed in the Nedd4 heterozygous mice.

The consolidation of short-term memory into long-term memory involves changing protein level and activity for the synaptic plasticity required for long-term potentiation (LTP). AMPA receptor trafficking is a key determinant of LTP and recently ubiquitination by Nedd4 has been shown to play an important role via direct action on the GluA1 subunit, although the physiological relevance of these findings are yet to be determined. We therefore investigated learning and memory in Nedd4+/− mice that have a 50% reduction in levels of Nedd4. These mice showed decreased long-term spatial memory as evidenced by significant increases in the time taken to learn the location of and subsequently find a platform in the Morris water maze. In contrast, there were no significant differences between Nedd4+/+ and Nedd4+/− mice in terms of short-term spatial memory in a Y-maze test. Nedd4+/− mice also displayed a significant reduction in post-synaptic LTP measured in hippocampal brain slices. Immunofluorescence of Nedd4 in the hippocampus confirmed its expression in hippocampal neurons of the CA1 region. These findings indicate that reducing Nedd4 protein by 50% significantly impairs LTP and long-term memory thereby demonstrating an important role for Nedd4 in these processes.