Learning and memory are encoded within the brain as biochemical and physical changes at synapses that alter synaptic transmission, a process known as synaptic plasticity. Although much is known about factors that positively regulate synaptic plasticity, very little is known about factors that negatively regulate this process. Recently, the signaling protein RGS14 (Regulator of G protein Signaling 14) was identified as a natural suppressor of hippocampal-based learning and memory as well as synaptic plasticity within CA2 hippocampal neurons. RGS14 is a multifunctional scaffolding protein that integrates unconventional G protein and mitogen-activated protein (MAP) kinase signaling pathways that are themselves key regulators of synaptic plasticity, learning, and memory. Here, we highlight the known roles for RGS14 in brain physiology and unconventional G protein signaling pathways, and propose molecular models to describe how RGS14 may integrate these diverse signaling pathways to modulate synaptic plasticity in CA2 hippocampal neurons.
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