Synaptic plasticity within the hippocampus is highly correlated with encoding episodic memories and cognition in humans, and this ability of neurons to strengthen/weaken synaptic inputs has been well studied at CA3-CA1 synapses. Inputs from CA3 Schaffer collaterals form synapses on proximal dendrites of both CA2 and CA1 pyramidal neurons, but CA2 neurons resist long-term potentiation (LTP), the strengthening of synaptic connections, following protocols that produce LTP in CA1 neurons. The molecular mechanisms regulating plasticity in CA2 neurons and the role of area CA2 in overall hippocampal function and behavior are not known. Regulator of G Protein Signaling 14 (RGS14) is a signaling protein that is highly enriched in the dendrites and spines of CA2 pyramidal neurons that is a natural suppressor of LTP. Mice lacking RGS14 mRNA/protein (RGS14-KO) display a robust and nascent capacity for LTP in CA2, with no effect on plasticity in area CA1. RGS14-KO mice also have enhanced hippocampal-dependent learning and memory relative to wild- type littermates. Taken together, these data show that RGS14 is a natural suppressor of CA2 synaptic plasticity and learning and memory. However, the mechanism(s) by which RGS14 limits LTP in area CA2 are not understood. RGS14 is a complex scaffold/effector that integrates G protein and H-Ras/MAPK signaling pathways to suppress ERK signaling. Consistently, application of a MEK inhibitor blocks the nascent LTP observed in area CA2 of RGS14-KO mice. Previous work had suggested robust calcium handling and extrusion underlie the lack of plasticity observed in area CA2, but until very recently, no defined connection between RGS14 and calcium signaling relevant to plasticity. New data shows that RGS14 interacts with the key intracellular calcium sensor calmodulin (CaM) in a calcium-dependent manner. Postsynaptic calcium entry is required for typical activity- dependent plasticity induction. Following calcium influx, calcium binds CaM (Ca2+/CaM) to initiate several downstream signaling cascades required for LTP induction. Specifically, CaM activates CaM-dependent protein kinase II (CaMKII) and PKA. New evidences shows RGS14 is phosphorylated by CaMKII as well. Based on these findings, my working hypothesis is that CaM binding to and CaMKII phosphorylation of RGS14 alter its known functions, and RGS14 interacts with known calcium-activated pathways to suppress LTP in area CA2. I will test this hypothesis in the following specific aims.
In aim 1, I will test how CaM binding and CaMKII phosphorylation modulate RGS14 activiy.
In aim 2, I will determine how RGS14 interactions with CaM and CaMKII impact LTP induction in area CA2.
These studies will characterize new molecular mechanisms that underlie learning and memory. The results of these studies will also help us better understand how these cellular processes are affected in human diseases such as bipolar disorder and autism.