Lack of Nerve Cell Coordination May Cause Fragile X Cognitive Inflexibility

The intellectual disabilities in people with fragile X syndrome may be caused by poor communication between neurons, rather than flaws in the nerve cells, according to research from New York University.

A research team there discovered that groups of neurons failed to signal in unison when mice with the condition were presented with contradictory information. Such coordinated nerve cell activity is crucial for many brain functions.

“The genetic defect that causes the most widespread form of intellectual disability and autism is surprisingly characterized by normally functioning memory and cognition-encoding neurons,” André Fenton, senior author of the paper, said in a press release. Fenton is a professor in the University’s Center for Neural Science.

“But despite being individually normal, these neurons are abnormal in their interactions, which results in cognitive impairments.”

In the study, “Normal CA1 Place Fields but Discoordinated Network Discharge in a Fmr1 -Null Mouse Model of Fragile X Syndrome,” researchers examined mice with the genetic flaw causing fragile X — a mutation in the FMR1 gene, which prevents the formation of the FMRP protein.

To study how the animals’ neurons were working, they employed a behavior test known as “place avoidance.” In the test, mice are allowed to learn to avoid a specific location. Earlier studies show that mouse models of the disease do have the ability to learn which place to avoid.

But in the next step of the experiment, researchers switch the location to test the animals’ cognitive flexibility. Normal mice swiftly learn to adapt to the new circumstances. Mice with fragile X failed to do so, results, published in the journal Neuron, showed.

To examine why, researchers looked at how the animals’ neurons worked in these circumstances. They focused their efforts on a brain region called the hippocampus, which is crucial for memory and learning.

The team found that individual neurons worked just fine. But they failed to signal together in a coordinated manner, making the signal weak.

Some researchers believe that fragile X is caused by a lack of functioning synapses.

But the data show that the intellectual disability in fragile X is not simply caused by abnormal synaptic connections — the chemical signals that transfer signals between neurons. Rather, it is the inability of individual neurons to signal together — a brain network flaw — that causes the cognitive inflexibility, researchers said.

“The good news, however, is we now have a better place to look for remedies: we can pursue a therapeutic strategy that targets neuronal interactions rather than the proximal molecular effects of a genetic mutation,” said Fenton.