Fewer ‘Sensing Antennas’ in Brain Nerve Cells May Contribute to Fragile X, Mouse Study Asserts
Having fewer primary cilia — cellular structures that act like antennas to detect several signals — in nerve cells may contribute to learning and memory deficits in fragile X syndrome, according to a study in mice.
These findings suggest that therapeutic approaches designed to increase the number of these sensing structures, which are essential for the growth and maturation of nerve cells in the brain, may be beneficial for people with the disorder.
“If we get to know how the primary cilia work in the newborn neuron and how they contribute to Fragile X syndrome, the next step would be to promote them,” Hye Young Lee, PhD, said in a press release. Lee is the study’s senior author and a professor at University of Texas Health Science Center at San Antonio.
“There are drugs to do that, and they could be potential therapies for Fragile X syndrome and other neurodevelopmental disorders, because there are multiple studies showing that neurodevelopmental disorders and autism can be reversed in adults,” Lee said.
The study, “Primary Ciliary Deficits in the Dentate Gyrus of Fragile X Syndrome,” was published in the journal Stem Cell Reports.
Fragile X, the leading genetic cause of autism, is caused by low-to-no levels of the fragile X mental retardation protein (FMRP), due to mutations in the FMR1 gene. FMRP, highly present in the brain, regulates the production of several other proteins, including at synapses (where nerve cells communicate).
Previous studies showed that the loss of FMRP in fragile X patients and in a mouse model of the disease is associated with structural changes in nerve cells. In mice, such changes were observed in newborn neurons of the dentate gyrus of the hippocampus, a brain region with a major role in learning and memory.
The dentate gyrus also is one of the two areas of the brain where neurogenesis, or the production of new nerve cells, continues to occur throughout life.
Interestingly, the loss of primary cilia also is associated with structural changes and impaired maturation of newly formed nerve cells of the dentate gyrus, as well as hippocampus-dependent learning and memory deficits.
“Although growing evidence indicates that primary cilia are implicated in brain development and intellectual disabilities, the functional role of primary cilia in neurodevelopmental disorders, such as fragile X syndrome (FXS) is largely unknown,” the researchers wrote.
Now, they identified, for the first time, a link between primary cilia and fragile X in a mouse model of the disease.
The team found that these mice had significantly fewer and shorter primary cilia in the dentate gyrus, compared with healthy mice. Notably, no changes in primary cilia were observed in other brain areas showing nerve cell deficits associated with cognitive problems.
Further analyses showed that a drop in primary cilia numbers was specific to granule neurons from the dentate gyrus’ subgranular zone (where neurogenesis occurs), and this deficiency was age dependent, starting at nearly two weeks after birth. Notably, granule neurons are among the most abundant and smaller nerve cells in the brain.
“We demonstrate that loss of FMRP leads to primary cilia deficits in a mouse model of FXS [Fragile X],” the scientists wrote, adding that these changes occur “at a specific time and location.”
Overall, such findings suggest that problems in primary cilia formation in newborn neurons of the dentate gyrus may contribute to the development of fragile X.
More studies are needed to identify FMRP targets and better characterize the molecular mechanisms underlying the primary cilia deficits. The team added that it would be interesting to assess whether primary cilia deficits also occur in the olfactory bulb, the other brain region where neurogenesis continues to occur.