Summary: Researchers have identified a novel role the RGS14 protein plays in limiting synaptic plasticity.
Source: Max Planck Florida Institute for Neuroscience.
The brain has an incredible capacity to support a lifetime of learning and memory. Each new experience fundamentally alters the connections between cells in the brain called synapses. To accommodate synaptic alterations, certain areas of the brain are highly plastic, meaning that have the ability to adapt to incoming information. Within an important brain structure for memory, the hippocampus, reside some of the most plastic cells in the entire brain, utilizing the process of synaptic plasticity to remain primed and flexible.
Nestled between the highly plastic CA1 and CA3 regions, the rather inflexible neurons of area CA2 do not readily undergo synaptic plasticity, sharply contrasting the functional properties of its close neighbors. Once underappreciated, the CA2 region is now understood to be important for social, spatial, and temporal aspects of memory as well as the target of caffeine’s cognitive boosting effects. Determining the unique factors that confer this unique resistivity to plasticity could provide vital insights into the neural basis of learning and memory.
Determined to elucidate this mystery of plasticity, researchers at the Max Planck Florida Institute for Neuroscience (MPFI) in collaboration with researchers at Emory University and the National Institute of Environmental Health Sciences, have for the first time identified a novel role for the CA2-enriched protein RGS14 and provided insights into the mechanism by which it limits plasticity. Paul Evans, Ph.D., a Post-doctoral Researcher in Ryohei Yasuda’s Lab, and collaborators, published a study in May 2018 in the journal eNeuro that links RGS14’s ability to curb plasticity to calcium regulation. RGS14, a specialized scaffolding protein, contains an amalgam of unique domains. Previous proteomics work by Evans and colleagues exploring these domains, established two new RGS14 interacting partners: CaMKII, a calcium signaling protein and Calmodulin, a calcium binding protein and crucial calcium regulator. To initiate the signaling cascade of synaptic plasticity in CA1 neurons, the influx of calcium into the cell is required to drive the activity of CaMKII and Calmodulin. Due to this relationship, RGS14 is poised to act as a calcium modulator, gating plasticity in CA2.
To verify this proposed relationship, Evans and collaborators probed in greater detail the masked form of plasticity, called Long-Term Potentiation (LTP), that is awoken in CA2 neurons when RGS14 is removed. Notably, mice lacking RGS14 display both enhanced learning in addition to robust CA2 synaptic plasticity, on par with levels reported in CA1. To ascertain if this latent CA2 plasticity is similar to the calcium-driven mechanisms of CA1, the team employed precise pharmacological inhibitors targeting critical calcium signaling molecules in mice lacking RGS14. Strikingly, the inhibitors abolished the newly unveiled LTP in CA2 neurons lacking RGS14, demonstrating the necessity of calcium signaling in CA2 and revealing similarities to the mechanisms that underlie plasticity in CA1.
Confirming calcium signaling as a critical component of quiescent plasticity in CA2, Evans next investigated calcium influx in small neuronal compartments called dendritic spines during LTP in CA2 neurons from mice containing and lacking RGS14. Calcium transients in spines from mice containing RGS14 were significantly smaller than those in mice lacking RGS14, indicating that RGS14 plays an important role in adjusting calcium levels in CA2 neurons. Furthermore, the acute overexpression of RGS14 in CA2 neurons lacking the protein once again abolished plasticity and significantly reduced plasticity when expressed in the CA1 region. Increasing extracellular calcium levels reversed the abolition of plasticity, reinforcing the notion that RGS14 exerts its plasticity restricting properties through the regulation of calcium.
“RGS14 seems to be special, acting as a molecular factor that puts the brakes on plasticity when it’s present, enabling specialized types of memory encoding. Establishing a greater understanding of the molecular makeup conferring subtle differences between brain regions, like those seen in CA1 and CA2, will allow us to better understand the mechanisms that underlie learning and memory,” notes Dr. Evans.
Funding: The work was done with support from the NIH/National Institute of Neurological Disorders and Stroke, NIH/National Institute of Environmental Health Sciences, NIH/National Institute of Mental Health, Max Planck Society.
Source: Helena Decker – Max Planck Florida Institute for Neuroscience
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to Max Planck Florida Institute for Neuroscience.
Original Research: Abstract for “RGS14 Restricts Plasticity in Hippocampal CA2 by Limiting Postsynaptic Calcium Signaling” by Paul R. Evans, Paula Parra-Bueno, Michael S. Smirnov, Daniel J. Lustberg, Serena M. Dudek, John R. Hepler and Ryohei Yasuda in eNeuro. Published May 21 2018.
RGS14 Restricts Plasticity in Hippocampal CA2 by Limiting Postsynaptic Calcium Signaling
Pyramidal neurons in hippocampal area CA2 are distinct from neighboring CA1 in that they resist synaptic long-term potentiation (LTP) at CA3 Schaffer Collateral synapses. Regulator of G Protein Signaling 14 (RGS14) is a complex scaffolding protein enriched in CA2 dendritic spines that naturally blocks CA2 synaptic plasticity and hippocampus-dependent learning, but the cellular mechanisms by which RGS14 gates LTP are largely unexplored. A previous study has attributed the lack of plasticity to higher rates of calcium (Ca2+) buffering and extrusion in CA2 spines. Additionally, a recent proteomics study revealed that RGS14 interacts with two key Ca2+-activated proteins in CA2 neurons: calcium/calmodulin, and CaMKII. Here, we investigate whether RGS14 regulates Ca2+ signaling in its host CA2 neurons. We find the nascent LTP of CA2 synapses due to genetic knockout (KO) of RGS14 in mice requires Ca2+-dependent postsynaptic signaling through NMDA receptors, CaMK, and PKA, revealing similar mechanisms to those in CA1. We report RGS14 negatively regulates the long-term structural plasticity of dendritic spines of CA2 neurons. We further show that wild-type (WT) CA2 neurons display significantly attenuated spine Ca2+ transients during structural plasticity induction compared with the Ca2+ transients from CA2 spines of RGS14 KO mice and CA1 controls. Finally, we demonstrate that acute overexpression of RGS14 is sufficient to block spine plasticity, and elevating extracellular Ca2+ levels restores plasticity to RGS14-expressing neurons. Together, these results demonstrate for the first time that RGS14 regulates plasticity in hippocampal area CA2 by restricting Ca2+ elevations in CA2 spines and downstream signaling pathways.
Significance Statement Recent studies of hippocampal area CA2 have provided strong evidence in support of a clear role for this apparently plasticity-resistant subregion of the hippocampus in social, spatial, and temporal aspects of memory. Regulator of G Protein Signaling 14 (RGS14) is a critical factor that inhibits synaptic plasticity in CA2, but the molecular mechanisms by which RGS14 limits LTP remained unknown. Here we provide new evidence that RGS14 restricts spine calcium (Ca2+) in CA2 neurons and that key downstream Ca2+-activated signaling pathways are required for CA2 plasticity in mice lacking RGS14. These results define a previously unrecognized role for RGS14 as a natural inhibitor of postsynaptic Ca2+ signaling in hippocampal area CA2.