The most common genetic disorder that can cause an inherited form of autism and intellectual impairment is the Fragile X syndrome (FXS). Brain researchers know the gene defect that causes FXS, and the damage it does: misshaping the brain’s synapses, the connections between neurons. However, UCLA researchers believe they know. The findings of a new study may lead to treatments that could quiet the excessive activity and allow for more normal behavior. The study was published on June 2 in the journal Nature.
The researchers studied a mouse that had FXS; they recorded the activity of networks of neurons in the living mouse brain while the animal was both awake and asleep. They found these neuronal networks showed too much activity, firing too often and in synch, much more than a normal brain. This neuronal excitability may also be the basis for symptoms in children with FXS, which can include disrupted sleep, seizures, or learning disabilities.
The results appear in the June 2 online edition of the journal Nature Neuroscience.
According to the National Fragile X Foundation, in males, approximately 1 in 3,600 to 4,000 have the disorder; it occurs less often in females: 1 in 4,000 to 6,000. The disorder is caused by a mutation in the gene fmr1, which encodes the fragile X mental retardation protein, FMRP. That protein is believed to be important for the formation and regulation of synapses. Mice that lack the fmr1 gene (and therefore lack the FMRP protein) show some of the same symptoms of human FXS, including seizures, impaired sleep, abnormal social relationships, and learning defects.
“We wanted to find the link between the abnormal structure of synapses in the FXS mouse, and the behavioral abnormalities at the level of brain circuits; that had not been previously established,” explained senior author Dr. Carlos Portera-Cailliau, an associate professor in the departments of neurology and neurobiology. He added, “So we tested the signaling between different neurons in fragile X mice, and indeed found there was abnormally high firing of action potentials, the signals between neurons, and also abnormally high synchrony; that is, too many neurons fired together. That’s a feature that is common in early brain development, but not in the adult.” “In essence, this points to a relative immaturity of brain circuits in FXS,” added Tiago Gonçalves, a former post-doctorate research in Dr. Portera-Cailliau’s lab and first author of the study.
The researchers used two-photon calcium imaging and patch-clamp electrophysiology, two sophisticated technologies that allowed the researchers to record the signals from individual brain cells. Abnormally high firing and network synchrony, said Dr. Portera-Cailliau, is evidence of the fact that neuronal circuits are over excitable in FXS. He added, “That likely leads to aberrant brain function or impairments in the normal computations of the brain,” he said. “For example, high synchrony could lead to seizures; more neurons firing together could cause entire portions of the brain to fire synchronously, which is the basis of seizures.” He noted that epilepsy occurs in up to 20% of children with FXS.
High firing rates could also impair the ability of the brain to decode sensory stimuli, by causing an overwhelming response to even simple sensory stimuli; that could lead to autism and the withdrawal from social interactions. Dr. Portera-Cailliau noted, “Interestingly, we found that the high firing and synchrony were especially apparent at times when the animals were asleep. This is curious because a prominent symptom of FXS is disrupted sleep and frequent awakenings.” And, he noted, since sleep is important for encoding memories and consolidating learning, this hyperexcitability of brain networks in FXS may interfere with the process of laying down new memories, and perhaps explain the learning disability in children with FXS. “Because brain scientists know a lot about the factors that regulate neuronal excitability, including inhibitory neurons, they can now try to use a variety of strategies to dampen neuronal excitation. Hopefully, this may be helpful to treat symptoms of FXS,” he said.
Dr. Portera-Cailliau noted that the next step in the research would be to explore whether fragile X mice indeed exhibit exaggerated responses to sensory stimuli. “Because an overwhelming reaction to a slight sound or caress, or hyperarousal to sensory stimuli, could be common to different types of autism, and not just FXS,” he said. “If hyperexcitability is the brain network basis for these symptoms, then reducing neuronal excitability with certain drugs that modulate inhibition could be of therapeutic value in these devastating neurodevelopmental disorders.”