The Role of RGS14 in Learning, Memory, and SynapticPlasticity

The hippocampus is crucial for converting new experiences into long- term memories following initial learning. Learning and memory are closely linked to synaptic plasticity, which involves altering the strength of connections between of neurons especially within the dentate gyrus (DG)-CA3-CA1 trisynaptic circuit of the hippocampus. Conspicuously absent from this circuit is the intervening CA2 whose existence as a distinct region has been subject to debate. The CA2 only recently been implicated in learning and memory. CA2 neurons have a striking lack of synaptic long-term potentiation (LTP). RGS14 is differentially expressed during postnatal development and is highly enriched in CA2 pyramidal neurons. RGS14 is critically important for suppressing synaptic plasticity in these cells and hippocampal learning and memory. RGS14 is an unusual scaffolding protein that integrates G protein and MAP kinase signaling pathways making it well positioned to suppress plasticity in CA2 neurons. Supporting this idea, we find that deletion of exons 2-7 of the RGS14 gene yields mice that lack RGS14 (RGS14-KO) that also express robust LTP following high frequency stimulation of Schaffer collateral synapses, but with no impact on synaptic plasticity in CA1 neurons. When tested behaviorally, RGS14-KO mice exhibited marked enhancement in the acquisition of spatial learning and of object recognition memory compared with their wild type littermates, but showed no differences in their performance on tests of non-hippocampal-dependent behaviors. These results demonstrate that RGS14 is a key regulator of signaling pathways linking synaptic plasticity in CA2 pyramidal neurons to hippocampal-based learning and memory, and RGS14 may serve as a memory filter that could be a pharmacological target to provide general cognitive enhancement in patients with neurodegenerative disorders.