Scientists Identify Critical New Protein Complex Involved in Learning and Memory

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified a protein complex that plays a critical but previously unknown role in learning and memory formation.

The study, which showed a novel role for a protein known as RGS7, was published April 22, 2014 in the journal eLife, a publisher supported by the Howard Hughes Medical Institute, the Max Planck Society and the Wellcome Trust.

“This is a critical building block that regulates a fundamental process—memory,” said Kirill Martemyanov, a TSRI associate professor who led the study. “Now that we know about this important new player, it offers a unique therapeutic window if we can find a way to enhance its function.”

The team looked at RGS7 in the hippocampus, a small part of the brain that helps turn short-term memory in long-term memory.

The scientists found the RGS7 protein works in concert with another protein, R7BP, to regulate a key signaling cascade that is increasingly seen as a critical to cognitive development. The cascade involves the neurotransmitter GABA, which binds to the GABAb receptor and opens inhibitory channels known as GIRKs in the cell membrane. This process ultimately makes it more difficult for a nerve cell to fire.

The image labeled brain slices and a graph from the study. The caption best describes the image.
Change in subcellular localization of RGS7 in the hippocampus of the R7bp−/− mice.
Electron micrographs of the stratum radiatum of the hippocampal CA1 region showing immunoparticles for RGS7, as detected using a pre-embedding immunogold method. Dendritic spines (s) and axon terminals (at) are marked. Arrows indicate locations of immunoparticles at the plasma membrane, while arrowheads identify RGS7 immunoparticles found just below the membrane. Quantitative analysis showed that RGS7 is less frequently detected in the plasma membrane, and accumulates within the first 100 nm from the plasma membrane, samples from R7bp−/− mice, *p<0.05, One-way ANOVA followed by the Bonferroni’s post hoc test, n = 3 mice. Scale bar: 0.2 μm. Credit Ostrovskaya et al/eLife.

This process turned out to be critical to normal functioning, as the research showed mice lacking RGS7 exhibited deficits in learning and memory.

Martemyanov believes the findings could ultimately have broad therapeutic application. “GIRK channels are implicated in a range of neuropsychiatric conditions, including drug addiction and Down’s syndrome, that result from a disproportionate increase in neuronal inhibition as a result of greater mobilization of these channels,” he said. “Now that we know the identity of the critical modulator of GIRK channels we can try to find a way to increase its power with the hopes of reducing the inhibitory overdrive, and that might potentially alleviate some of the disruptions seen in Down’s syndrome. It is possible that similar strategies might apply for dealing with addiction, where adaptations in the GABAb-GIRK pathway play a significant role.”

Targeting the RGS7 protein could allow for better therapeutic outcomes with fewer side effects because it allows for fine tuning of the signaling, according to Olga Ostrovskaya, the first author of the study and a member of Martemyanov’s lab, who sees many ways to follow up on the findings.

“We’re looking into how RGS7 is involved in neural circuitry and functions tied to the striatum, another part of the brain responsible for procedural memory, mood disorders, motivation and addiction,” Ostrovskaya said. “We may uncover the RGS7 regulation of other signaling complexes that may be very different from those in hippocampus.”

Notes about this neuroscience research

In addition to Ostrovskaya and Martemyanov, other authors of the study, “RGS7/Gβ5/R7BP Complex Regulates Synaptic Plasticity and Memory by Modulating Hippocampal Gababr-Girk Signaling,” include Keqiang Xie and Ikuo Masuho of TSRI; Ana Fajardo-Serrano and Rafael Lujan of the Universidad de Castilla-La Mancha, Albacete, Spain; and Kevin Wickman of the University of Minnesota.

The study was supported by the National Institutes of Health (Grants DA021743, DA026405, MH061933, DA034696, HL105550) and by grants from the Spanish Ministry of Education and Science (BFU-2012-38348) and CONSOLIDER (CSD2008-00005).

Contact: Eric Sauter – Scripps Research Institute
Source: Scripps Research Institute press release
Image Source: The image is credited to Ostrovskaya et al/eLife and is adapted from the open access research paper
Original Research: Full open access research for “RGS7/Gβ5/R7BP complex regulates synaptic plasticity and memory by modulating hippocampal GABABR-GIRK signaling” by Olga Ostrovskaya, Keqiang Xie, Ikuo Masuho, Ana Fajardo-Serrano, Rafael Lujan, Kevin Wickman, and Kirill A. Martemyanov in eLife. Published online April 22 2014 doi:10.7554/eLife.02053

Open Access Neuroscience Abstract

RGS7/Gβ5/R7BP complex regulates synaptic plasticity and memory by modulating hippocampal GABABR-GIRK signaling

In the hippocampus, the inhibitory neurotransmitter GABA shapes the activity of the output pyramidal neurons and plays important role in cognition. Most of its inhibitory effects are mediated by signaling from GABAB receptor to the G protein-gated Inwardly-rectifying K+ (GIRK) channels. Here, we show that RGS7, in cooperation with its binding partner R7BP, regulates GABABR-GIRK signaling in hippocampal pyramidal neurons. Deletion of RGS7 in mice dramatically sensitizes GIRK responses to GABAB receptor stimulation and markedly slows channel deactivation kinetics. Enhanced activity of this signaling pathway leads to decreased neuronal excitability and selective disruption of inhibitory forms of synaptic plasticity. As a result, mice lacking RGS7 exhibit deficits in learning and memory. We further report that RGS7 is selectively modulated by its membrane anchoring subunit R7BP, which sets the dynamic range of GIRK responses. Together, these results demonstrate a novel role of RGS7 in hippocampal synaptic plasticity and memory formation.

“RGS7/Gβ5/R7BP complex regulates synaptic plasticity and memory by modulating hippocampal GABABR-GIRK signaling” by Olga Ostrovskaya, Keqiang Xie, Ikuo Masuho, Ana Fajardo-Serrano, Rafael Lujan, Kevin Wickman, and Kirill A. Martemyanov in eLife April 22 2014 doi:10.7554/eLife.02053.

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