Inflexible Learning Disability in Fragile X Syndrome Explained in New Mouse Study

Mice with the genetic defect that causes fragile X syndrome (FXS) are unable to learn new information that contradicts what they initially learned, researchers at NYU and the State University of New York report.

The study, “Control of recollection by slow gamma dominating mid-frequency gamma in hippocampus CA1,” appeared in the journal PLOS Biology.

Fragile X is the most frequent single-gene cause of autism and intellectual disability. People with FXS frequently experience deficits in thinking, reasoning, and memory, particularly in working memory, which involves the temporary ability to store, manipulate, and retrieve information.

“These findings suggest that neural circuits in FXS may be fundamentally intact but improperly tuned, which results in inflexibility in gaining certain types of knowledge,” André Fenton, PhD, the study’s senior author, said in a press release. Fenton is a professor at the Center for Neural Science at NYU.

The researchers focused on the hippocampus, which is a crucial brain area in learning and memory, including spatial memory, which requires both encoding and the recollection of information.

But the neural events that regulate whether hippocampal neurons remember past information or encode new experiences into the memory are unknown. This is especially relevant because the same neurons are involved in both processes.

In their study, the scientists identified a “signature of recollection” in a specific area of the hippocampus – the CA1. This electrophysiological mapping, which refers to the brain’s electrical activity, clarified whether the neurons are remembering information or encoding current experience into memory.

Results showed that encoding and recollecting result from a balance between two types of synaptic activity – collectively defined as rhythmic activity – in the hippocampus. The researchers found that encoding is the result of fast rhythmic activity overwhelming slower rhythmic activity. But remembering information happens when the slower rhythm dominates the medium rhythm.

The investigators also observed that the mouse model of fragile X syndrome – mice that didn’t carry the Fmr1 gene – shows an excessive amount of the slow rhythm.

As hippocampal neurons in these mice are normal, their learning and memory are similar to mice with normal cognition, called controls. However, the excess of slow rhythm causes an inability to learn new information that is contrary to what was initially learned. This prevents the cognitive flexibility exhibited by healthy mice.

Overall, the results “indicate that recollection occurs when CA1 slow [rhythm] dominates [medium rhythm] and that accurate recollection of inappropriate memories explains [the FXS mouse model’s] cognitive inflexibility,” researchers wrote.

“We now have a better understanding of a cognitive deficit that is characteristic of FXS – excessive recollection of the information that was once accurate and an inability to process corrective material,” Fenton added.