Imagine the chaos if all traffic lights suddenly went red in a city. The same can apply to the brain, which needs a regulated flow of information to learn and make memories. New research published in the 31 October issue of Cell unveils how a neural stop signal goes askew in neurofibromatosis, one of the most common genetic causes of learning disabilities in humans.
Neurofibromatosis typically produces fibrous lumps in nerve fibers, some of them visible on the skin. Common complications include high blood pressure, curvature of the spine, and specific learning problems, which are often related to spatial cognition. The condition is caused by mutations in a gene dubbed NF1, but the precise mechanism that lead to learning disabilities was not known until now.
To address that puzzle, Alcino Silva, a neuroscientist at the University of California, Los Angeles, has been experimenting with mice that have mutations in their NF1 gene. The scientists confirmed that these mice have learning problems by testing them in a Morris water maze, a common lab test of animal learning and memory. Through studying the brains of these mice, the team uncovered that the faulty gene inhibits neurons, by releasing excess of the neurotransmitter GABA.
Silva hypothesized that GABA's influence on synapses, physical connections between neurons, accounted for the learning disabilities caused by neurofibromatosis. "Memory is stored in the brain by subtle changes in synapses," he says. "Recalling a memory is reactivating a specific set of synapses." But in NF1-mutated mice, says Silva, too much GABA is produced, synapses are not allowed to change, and learning is inhibited.
To confirm this, Silva's team gave the NF1-mutated mice picrotoxin, a drug known to counteract GABA effects. That reversed the animals' learning disability in the water maze. It's unlikely that picrotoxin can be used in people due to its dangerous side effects, Silva says. But "the more we know about the mechanisms of learning disabilities, the more likely a treatment becomes."
Interfering with GABA signaling may require a delicate touch. Silva's team also found that in normal mice, spatial learning induces an increase in GABA. This, he says, shows that learning involves a delicate balance between excitation and inhibition, "just like red lights are essential to keep traffic flowing." Many researchers have focused on excitatory signals, notes neuroscientist Andreas Draguhn of the University of Heidelberg in Germany, but this new work emphasizes "the importance of inhibition for learning."