A molecule that can sense viruses and tumors in the body has another, surprising function in the brain—to finely tune the excitability of interconnected networks of neurons, thus enabling the biological imprint of experiences during the learning process. That was the finding from a team of researchers—including two faculty members from the Virginia Tech Carilion Research Institute—in a recent issue of Cell.
The molecule is a double-stranded RNA-activated protein kinase called PKR. When PKR was either genetically removed or pharmacologically inhibited, the activity of inhibitory synapses in the brains of adult mice was selectively reduced, while excitatory synapses function remained unaffected. PKR affects this action by targeting the release of packets of inhibitory chemical neurotransmitters from the presynaptic terminals in the brain’s hippocampus – an area located deep within the brain’s temporal lobes where memories are initially formed. The loss or reduction of PKR activity thus leads to an overall increase in the excitability of networks of neurons within the hippocampus. Such effects, if overly strong, are usually associated with epileptic seizures. In this case, however, the reduced level of synaptic inhibition led not only to increased excitability in the hippocampus (as well as in the cerebral cortex), but also to enhanced strengthening of excitatory synapses, facilitating learning and memory.
Michael Friedlander, executive director of the Virginia Tech Carilion Research Institute, and Hodja Kalikulov, a research assistant professor at the institute, conducted the part of the study that focused specifically on the selective effects of PKR on synaptic inhibition in the hippocampus, which made the induction of long-term synaptic potentiation and subsequent learning more efficient.
“The hippocampus plays a critical role in the formation of new memories, particularly those that involve spatial navigation,” said Friedlander, who is also a professor of biological sciences at Virginia Tech and a core faculty member in the School of Biomedical Engineering and Science at Virginia Tech. “It’s relatively easy, for example, to navigate your own home in the dark based on your brain’s stored spatial representation of where your furniture is located. If you need to negotiate an unfamiliar room in the dark, though, that process becomes more challenging unless you’ve had time to ‘learn’ the room’s geography. The hippocampus has neurons that—through their rich array of excitatory and inhibitory synaptic connections—code for one’s relative position in such an environment through a learning process that forms what are called ‘place maps.’ Indeed, even individual cells in this area of the brain have ‘place fields’ that allow them to generate trains of nerve impulses when the mouse—or person—is located in a certain position within the room.”
Friedlander added that the scientists were surprised to see such a selective action of this molecule on the inhibitory synaptic transmission process and its dramatic effect on synaptic plasticity and learning. “It never ceases to amaze me as to how little we understand about how the brain works and how nature uses similar genes and molecules in such diverse functions as fighting infection and cancer, and enhancing learning and memory,” he said. “But maybe we shouldn’t be that surprised since molecular memory of viruses and recognition of tumor cells may have more in common with the types of memories we form in the brain such as recognizing faces or familiar paths.”
Friedlander points out that PKR activity is altered in a range of neurological disorders, such as Huntington’s disease and Parkinson’s disease. “This finding,” he said, “opens a door for the development of potentially new therapeutic tools.”
The study, published on December 9, represents a collaboration among several research teams, including the lead laboratory of Mauro Costa-Mattioli, an assistant professor of neuroscience at Baylor College of Medicine, where Friedlander served as chair of the Department of Neuroscience and director of neuroscience initiatives from 2005 to 2010.