Cellular mechanisms of synaptic plasticity in hippocampal area CA1

The coordinated activation of a number of neuronal activity-regulated kinases is required for the full expression of LTP. Modulating the efficacy of synaptic transmission, such as occurs in LTP and LTD, is thought to be a cellular mechanism for storing information in the brain. In particular, a variety of pharmacological and genetic studies have established important roles for CaMKII and ERK in excitatory synaptic plasticity, as well as hippocampal-dependent memory formation [1-3]. In hippocampal area CAl, CaMKII activity increases synaptic strength by two known mechanisms: modification of AMP AR channel properties [4] and regulation of AMPAR trafficking [5]. The ERK pathway also contributes to synaptic strengthening, in part through the regulation of mRNA translation [6], as well as through regulation of AMPAR trafficking mediated by the Ras pathway [5, 7]. As opposed to the classical routes for ERK activation in many cell types by growth factors, a calcium-dependent pathway upstream of Ras triggers the activation of ERK during NMDA receptor-dependent LTP in neurons, but precisely how this occurs remained unexplained. Previous investigations have focused on CaMKII as a potential mediator of calcium-dependent ERK activation in via the Ras GTPase activator SynGAP, but recent studies fail to support this hypothesis [8-11]. Interesting! y, the CaMKK/CaMKI pathway was recently shown to mediate depolarization-induced activation ofERK via Ras in NG-108 cells [12]. Therefore, it was important to determine whether ERK can be similarly regulated by CaMKK/CaMKI in neurons, and to determine whether this pathway provides a biochemical link between the calciumpermeable NMDA receptor and ERK activation, which is required for the full expression