A quarterly publication of the Autism Research Institute

The Autism Research Review International is quarterly publication of the Autism Research Institute

Fall, 2017 | Number 4, Volume 31

Ubiquitin gene defect leads to excess of cerebellar synapses

An excess of brain synapses—the connections between cells that allow them to signal one other—may be a key factor in autism, according to new research. 

Pamela Valnegri and colleagues investigated six genes that attach a molecular tag called ubiquitin to proteins. These genes tell a cell what to do with the proteins—for instance, whether to discard them or reroute them to another area of the cell. Previous research has linked defects in ubiquitin genes to autism. 

To study how ubiquitin genes affect brain development, the researchers removed the ubiquitin gene RNF8 in neurons in the cerebellum—a brain region affected by autism—of young mice. They found that neurons lacking the RNF8 protein formed about 50 percent more synapses. This doubled the strength of signals received by cells. (Research conducted after the publication of the study revealed that inhibition of any of the ubiquitin genes can cause an increase in synapses in the cerebellum.) 

“This study raises the possibility that there may be too many synapses in the brains of patients with autism,” senior author Azad Bonni says. “You might think that having more synapses would make the brain work better, but that doesn’t seem to be the case. An increased number of synapses creates miscommunication among neurons in the developing brain that correlates with impairments in learning, although we don’t know how.” 

The researchers note that as the cerebellum plays a crucial role in movement and the learning of motor skills, an excess of synapses in this region may explain some symptoms of autism such as toe-walking and poor coordination. Consistent with this idea, the mice that lacked the RNF8 gene had difficulty learning motor skills. In addition, the cerebellum is involved in higher cognitive functions that are impaired in autism, such as language and attention. 

Bonni says that if the researchers’ findings are replicated, “then you can start looking at ways of controlling the number of synapses. It could potentially benefit not just people who have these rare mutations in ubiquitin genes but other patients with autism.” 


Citations

“RNF8/UBC13 ubiquitin signaling suppresses synapse formation in the mammalian brain,” P. Valnegri, J. Huang, T. Yamada, Y. Yang, L. A. Mejia, H. Y. Cho, A. Oldenborg, and A. Bonni, Nature Communications, Vol. 8, No. 1, November 2, 2017. Address: Azad Bonni, Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, [email protected]

—and— 

“In autism, too many brain connections may be at root of condition,” news release, Washington University School of Medicine, November 2, 2017.