 Underlying the brain's remarkable ability to adapt to new information is the process known as synaptic plasticity, but not all parts of the brain are plastic. Some regions appear highly resistant to this activity, such as hippocampal region CA2, an area with a central role in the social, spatial and temporal aspects of memory. The protein RGS14 has been shown to naturally block plasticity in CA2 neurons, but precisely how it accomplishes this has remained a mystery. Now, researchers at the Max Planck Institute for Neuroscience in Florida, collaborating with teams at Emory University and the National Institute of Environmental Health Sciences, have uncovered a unique role for RGS14 in inhibiting calcium signalling in CA2 neurons, providing new insights into how plasticity is regulated. The teams reached this conclusion by examining synaptic potentiation, thought to be the cellular substrate of memory formation. In brain slices prepared from RGS14 knockout and wild-type adult mice. Intriguingly, mice lacking RGS14 show enhancements in learning and memory and possess unusual CA2 plasticity, which is normally absent in wild-type mice. The mice were crossed with a reporter line that fluorescently labelled CA2 neurons to help localize synapses onto these cells for physiology studies. Using field potential recordings, the teams showed that robust long-term potentiation could be induced in the knockout mice, but not the wild-type controls. Calcium entry into neurons is a crucial step in synaptic plasticity, and one area in which CA2 neurons show different properties than their plastic neighbors in CA1. To examine the relationship between RGS14 expression and calcium influx, the scientists treated brain slices with pharmacological inhibitors of the NMDA receptor as well as carmodulin-dependent protein kinase and protein kinase A signaling. The results showed that CA2 neurons lacking RGS14 required activity from all three pathways to achieve synaptic potentiation, revealing a striking similarity to the calcium-driven mechanisms that underlie long-term potentiation in CA1. Having confirmed a role for calcium-driven signaling in the nascent plasticity of CA2 neurons lacking RGS14, the team next investigated the role of calcium flux in the diminished plasticity of wild-type CA2 neurons. They found that the peak elevations in calcium evoked by glutamate uncaging were significantly smaller in spines from the wild-type neurons than in those lacking RGS14. Uncaging also elicited significantly smaller calcium transients in the dendrites of the wild-type neurons. These findings indicate that RGS14 modulates calcium levels in CA2 neurons during synaptic activity. To further investigate whether RGS14 reduces the capacity for spine plasticity, the team overexpressed the protein in slice cultures prepared from the knockout mice. The overexpression significantly blocked the induction of spine plasticity in both CA2 and CA1 neurons. Strikingly, increasing the extracellular concentration of calcium reversed the blockade, further supporting the idea that calcium signaling is central to RGS14's role in restricting structural plasticity of dendritic spines. These findings are the first to functionally implicate RGS14 as a regulator of calcium signaling in CA2 neurons. By identifying new mechanisms through which plasticity is gated by RGS14, in this recently appreciated region of the brain, this work brings us one step closer to understanding how CA2 neurons may resist plasticity to help encode specific types of long-term memory.