Neuronal MEK is important for normal fear conditioning in mice.

The extracellular signal-regulated kinase (ERK) cascade has received much attention for its possible role in neuronal synaptic plasticity. Although ERK activation has been linked to learning behaviors and activity-dependent neuronal function, much of the acquired data has relied upon pharmacological agents that suppress ERK function in both neurons and nonneuronal cells. To determine the function of neuronal ERK activity in learning, a new line of transgenic mice was generated wherein dominant-negative MEK1, the upstream obligate activator of ERK1/2, was expressed by using a neuronal-specific and pan-neuronal Talpha1 alpha-tubulin promoter element. Mice expressing this construct exhibited decreased ERK1/2 activity in the hippocampus and thus were tested for learning impairments. In a battery of control tests, including open field, rotarod, and shock threshold, the transgenic mice displayed no deficits and performed as well as their wild-type littermate counterparts. However, the mice displayed a significant impairment in contextual fear conditioning compared with the wild-type littermates. These findings indicate that the MEK1/ERK1/2 cascade within neurons plays an important role in the processes of learning and memory.