Synaptic firing in a neural network is the key to learning and memory. Learning and memory are both a function of the synaptic plasticity.
Researchers at Johns Hopkins have discovered in mice a molecular wrecking ball that powers the demolition phase of a cycle that occurs at synapses — those specialized connections between nerve cells in the brain — and whose activity appears critical for both limiting and enhancing learning and memory. The newly revealed protein, which the researchers named thorase after Thor, the Norse god of thunder, belongs to a large family of enzymes that energize not only neurological construction jobs but also deconstruction projects. The discovery is described in the April 15 issue of Cell. “Thorase is vital for keeping in balance the molecular construction-deconstruction cycle we believe is required for memory formation,” explains Valina Dawson, professor of neurology and neuroscience in the Johns Hopkins Institute of Cell Engineering. “It’s a highly druggable target, which, depending on whether you enhance or inactivate it, may potentially result in new treatments for autism, PTSD, and memory dysfunction.”
The enzyme is one of many AAA+ ATPases that drive the assembly of proteins needed to form specialized receptors at the surfaces of synapses. These receptors are stimulated by neighboring neurons, setting up the signaling and answering connections vital to brain function. The Hopkins team showed how thorase regulates the all-important complementary process of receptor disassembly at synapses, which ultimately tamps down signaling. Prolonged excitation or inhibition of these receptors — due to injury, disease, genetic malfunction or drugs — has been implicated in a wide array of learning and memory disorders.
They discovered that the more thorase, the quicker the scaffolding deconstructed and the faster the surface receptors decreased. To see if the deconstruction of the protein complex had any effect on nerve-signaling processes, they again used cells to record receptor activity by measuring electric currents as they fluxed through cells with and without thorase. In the presence of extra thorase, surface receptor expression was decreased, resulting in reduced signaling. Next, the team measured the rates of receptor recycling by tagging the protein complex with a fluorescent marker. It could then be tracked as it was subsequently reinserted back into the surface membrane of a cell. In cells in which thorase was knocked out, there was very little deconstruction/turnover compared to normal cells. The scientists reversed the process by adding back thorase. Finally, the team conducted a series of memory tasks in order to compare the behaviors of normal mice with those genetically modified to lack thorase. When the animals lacking thorase were put into a simple maze, their behaviors revealed they had severe deficits in learning and memory.
“Mice lacking thorase appear to stay in a constant state of stimulation, which prevents memory formation,” Dawson explains.