How a crucial protein aids learning and memory
Johns Hopkins researchers have studied the movement of the protein SynGap within brain cells and found that when SynGAP is released from dendrites, they grow larger which strengthens synapses and memory.
Researchers at Johns Hopkins have found out how a protein crucial to learning works — by removing a biochemical "clamp" that prevents connections between nerve cells in the brain from growing stronger. The finding moves neuroscientists a step closer to figuring out how learning and memory work, and how problems with them can arise.
A report on the discovery appeared January 7 in the journal Neuron.
Animals learn and form memories when synapse connections among brain cells form and grow strong. Researchers have known for a long time that a crucial step in the process is the flow of calcium ions into the synapse area.
Previous studies suggested the calcium activates a protein called CaMKII, but CaMKII's precise role in the process remained unknown.
"What happens next has been a mystery for 25 years," says Rick Huganir PhD, director of the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine.
To find CaMKII, research associate Yoichi Araki PhD, added chemicals to lab-grown neurons to spur them to form stronger connections and saw that at rest, a protein called SynGAP was concentrated in the dendritic spines that form synapses with other cells — a pattern previous experiments also had identified.
But once the synapse-strengthening process began, SynGAP flooded out of the dendritic spines. The spines then grew larger, strengthening synapse connections.
SynGAP is usually clamped to the "scaffolding" that gives dendritic spines their structure. Latched to the structure, it prevents the chain reaction of chemical signals known as Ras, which is needed for learning.
An influx of calcium into the synapse activates CaMKII, to unhook SynGAP from the cells' scaffolding and spurs Ras signaling to begin.
Studies at other institutions have identified mutations in the gene for SynGAP associated with autism and intellectual disability.
To see how these mutations affect SynGAP's function, the Johns Hopkins research team altered their lab-grown cells so that they could follow the outcomes on these mutations. All three of the disability-associated mutations showed similar effects: Compared to normal neurons, there was less SynGAP in synapses when they were at rest, and activating CaMKII did not noticeably change anything.
Huganir adds: "This gives us a much clearer idea of how some SynGAP mutations cause problems in the brain. The findings may one day lead to drugs or other interventions that would lessen the effects of mutations."
•SynGAP is dispersed from synapses by NMDAR and CaMKII activation
•SynGAP dispersion activates synaptic Ras and induces LTP
•Rapid dispersion of SynGAP predicts the maintenance of potentiated synapse
•SynGAP mutations found in intellectual disability disrupt this mechanism
SynGAP is a Ras-GTPase activating protein highly enriched at excitatory synapses in the brain. Previous studies have shown that CaMKII and the RAS-ERK pathway are critical for several forms of synaptic plasticity including LTP. NMDA receptor-dependent calcium influx has been shown to regulate the RAS-ERK pathway and downstream events that result in AMPA receptor synaptic accumulation, spine enlargement, and synaptic strengthening during LTP. However, the cellular mechanisms whereby calcium influx and CaMKII control Ras activity remain elusive. Using live-imaging techniques, we have found that SynGAP is rapidly dispersed from spines upon LTP induction in hippocampal neurons, and this dispersion depends on phosphorylation of SynGAP by CaMKII. Moreover, the degree of acute dispersion predicts the maintenance of spine enlargement. Thus, the synaptic dispersion of SynGAP by CaMKII phosphorylation during LTP represents a key signaling component that transduces CaMKII activity to small G protein-mediated spine enlargement, AMPA receptor synaptic incorporation, and synaptic potentiation.
Other authors on the paper are Menglong Zeng and Mingjie Zhang, both of Hong Kong University of Science and Technology.
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