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Apr 23, 2014

Molecule Found to Manage Signal Channels Irrigating Fields of Memory

  • Similar to the way crops need just the right flow of water to thrive, memories take hold and grow best when signaling pathways in the brain are well balanced. This is particularly true in the hippocampus, a small part of the brain that helps turn short-term memory into long-term memory. In the hippocampus, report scientists, a protein complex has been found to play a critical but previously unknown role in learning and memory formation. The scientists add that the finding may have therapeutic implications, particularly in alleviating the disruptions seen in Down syndrome and drug addiction.

    The scientists, who represent The Scripps Institute, say that a protein known as RGS7 works in concert with another protein, R7BP, to regulate a key signaling cascade that is increasingly seen as 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. (GIRKs stands for G protein-gated inwardly rectifying K+ channels.) This process ultimately makes it more difficult for a nerve cell to fire.

    To investigate this process, the researchers worked with mice lacking RGS7. The details of this work appeared April 22 in eLife, in an article entitled “RGS7/Gβ5/R7BP complex regulates synaptic plasticity and memory by modulating hippocampal GABABR-GIRK signaling.”

    In this article, the authors wrote: “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.”

    In other words, mice lacking RGS7 exhibited deficits in learning and memory, suggesting that the balancing of stimulation and deactivation is critical to normal functioning.

    Kirill Martemyanov, Ph.D., a TSRI associate professor who led the study, believes the findings could ultimately have broad therapeutic applications. “GIRK channels are implicated in a range of neuropsychiatric conditions, including drug addiction and Down 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 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, Ph.D., the first author of the study and a member of Dr. 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,” Dr. Ostrovskaya said. “We may uncover the RGS7 regulation of other signaling complexes that may be very different from those in hippocampus.”



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