Fragile X concept falters on amygdala check | Spectrum
Place, place: Glutamate receptors in a rat model of Fragile X syndrome overlap with presynaptic markers at synapses in the amygdala (above), but not in the hippocampus (below).
Activation of the activity of certain receptors in the amygdala reverses some features of Fragile X syndrome in a rat model of the disease, according to a new study.
The result contradicts the prevailing notion that overactive signaling by these receptors underlies the characteristics of the syndrome – and provides new clues as to why potential Fragile-X drugs have failed in clinical trials.
“It’s a really important paper,” said Randi Hagerman, medical director of the MIND Institute at the University of California, Davis, who was not involved in the work. “I think that we need to translate such research results into clinical studies on humans as soon as possible.”
Fragile X syndrome is the most common form of hereditary intellectual disability and is often accompanied by anxiety, seizures, and autism. It typically comes from mutations that silence a gene called FMR1, which inhibits the production of the protein it encodes, FMRP.
According to a long-held theory, the lack of FMRP overactivates a receptor called mGluR5, which in turn affects the ability of neurons to adjust the strength of their synaptic connections. The idea is largely based on findings from model mice: Compared to control mice, their synaptic connections between cells that do not fire synchronously in the hippocampus, an area of the brain that is important for learning and memory, become weaker more easily. Drugs that block mGluR5 appeared to normalize synaptic weakening and reverse properties in the mice, but these results did not ultimately translate into humans.
“One size doesn’t fit all,” says the lead researcher of the new work, Sumantra Chattarji, senior professor of neurobiology at the National Center for Biological Sciences in Bangalore, India.
The failure of the study made sense, says Chattarji, because mGluR5 doesn’t work in the same way throughout the brain. In the amygdala – an area that shapes fear and anxiety – mGluR5 mediates, according to previous studies, the strengthening rather than the weakening of synapses. Fragile X mice have a typical level of synaptic weakening in the amygdala, which Chattarji and colleagues noted in 2010, but they have an impaired ability to strengthen connections between synchronous neurons. And blocking mGluR5 there did not reverse the deficit.
“It annoyed me,” says Chattarji. “If the plasticity is the opposite, then we have a problem” in treatment.
For the new work, Chattarji and his colleagues studied synaptic plasticity in the amygdala using rats that lack a copy of FMR1. Rats have a larger amygdala than mice, which makes the experiments easier.
They trained the rats to associate a sound with a light electric shock to the foot. Unlike wild-type rats, fragile X rats do not freeze with fear when they hear the same sound a day later, the team found, suggesting that the animals’ fear memory is impaired. Fragile X rats also showed an atypical neural response to the sound, as evidenced by the recorded electrical signals from the animals’ amygdala.
The electrical stimulation of two neurons in close succession strengthened the synapses in sections of brain tissue from the amygdalae of wild-type rats – a type of plasticity that, according to previous research, can also be induced in the hippocampi of fragile X-mice. But plasticity failed in tissue sections from the amygdalae of fragile X rats and replicated the mouse findings from the 2010 paper.
The reason for the different reactions in the amygdala and hippocampus is initially unclear, says Chattarji. One indication, however, was that in the amygdala, mGluR5 is mainly located at the signal-sending ends of neurons, while in the hippocampus it is mainly located at the signal-receiving ends, the researchers found.
Activation of mGluR5 in sections of brain tissue from the amygdala of fragile X model rats reversed the deficits in synaptic plasticity, the new study showed. And the infusion of an mGluR5-activating drug into the amygdala of fragile X rats restored the fear memory of the animals and led to typical neuronal responses to the sound. The results were published in Cell Reports in October.
“If this is mainly how the amygdala works and not other parts of the brain, then” [activating mGluR5] may not be a very good treatment, ”said Elizabeth Berry-Kravis, a professor of pediatrics and neurology at Rush University Medical Center in Chicago, Illinois, who was not involved in the study. “It could make other areas worse.”
Chattarji and colleagues are talking to drug companies and exploring ways they could combine different types of drugs – some mGluR5 blockers, some activators, or some that use different mechanisms – to target multiple areas of the brain at once.
Some researchers, including Berry-Kravis, are instead looking for mechanisms that are downstream of mGluR5 and that can converge across areas of the brain.
Whether or not the new work suggests new treatments, it underscores the importance of studying amygdala dysfunction in fragile X syndrome and autism in general, says Eric Klann, director of the Center for Neural Science at New York University in New York City. Klann wasn’t involved in the new work, but he co-authored the 2010 study with Chattarji.
“I find [the lack of research in this area] surprising and disappointing, since the amygdala is the emotional center of the brain, ”says Klann, especially since people with Fragile X syndrome and autism often show atypical emotional behaviors.
In the future, Chattarji and colleagues plan to conduct similar analyzes and compare amygdala function with other animal models of autism.