An inherited form of intellectual disability, due to mutations in the SYNGAP1 gene, impairs connection of inhibitory neurons

Graziella Di Cristo and Jacques Michaud

Graziella Di Cristo and Jacques Michaud

Intellectual disability is characterized by significant impairment of cognitive and adaptive functions and affects 1-3 in 100 individuals worldwide. A few years ago, scientists at CHU Ste.Justine reported for the first time that genetic mutations in the gene SYNGAP1 cause a form of intellectual disability, which is often associated with autism spectrum disorders and epilepsy. Since then, DNA sequencing of SYNGAP1 in several groups of individuals with intellectual disability in Canada, the US and Europe has revealed that pathogenic mutations in SYNGAP1 are one of the most common cause of genetic intellectual disability.

SYNGAP1 regulates the way specialized cells of the brain, called neurons, communicate. There are two major types of neurons, those that excite (or activate) and those that inhibit other neurons. Recently, researchers at CHU Ste. Justine, in collaboration with Université de Montréal, have discovered that defective SYNGAP1 alters the formation of synapses, the specialized structures neurons use to communicate, by inhibitory neurons. In turn, these alterations in the inhibitory neurons cause deficits in memory and social behavior.

This finding, published in Nature Communications, provides new insights into the cellular causes of intellectual disability associated with SYNGAP1 mutations that may guide identification of new medications for the affected children.

This study was led by Graziella Di Cristo, a scientist at the Research Center of CHU Ste. Justine and an associate professor of Neuroscience at Université de Montréal, and Jacques Michaud, genetician, pediatrician and scientist at CHU Ste. Justine and professor of Pediatrics at Université de Montréal, in collaboration with Jean-Claude Lacaille, professor of Neuroscience at Université de Montréal.

Based on the discovery that SYNGAP1 mutations alters inhibitory communication, the labs at CHU Ste.Justine will now focus on searching therapeutic approaches for correcting this type of synapses. In particular, it will be critical to determine whether it is possible to improve intellectual disability in adults or if it will be necessary to start treatment in early infancy.

While mutations in SYNGAP1 are accountable for only a small percentage of individual with intellectual disability and related autism spectrum disorders and epilepsy, there is strong evidence that other intellectual disability, autism and epilepsy genes disrupt the development of inhibitory synapses. Therefore, finding safe approaches to restore inhibitory synapse growth and function will be a key step to treat this family of neurological disorders.

Original research article:

Berryer MH, Chattopadhyaya B, Xing P, Riebe I, Bosoi C, Sanon N, Antoine-Bertrand J, Lévesque M, Avoli M, Hamdan FF, Carmant L, Lamarche-Vane N, Lacaille JC, Michaud JL, Di Cristo G. Decrease of SYNGAP1 in GABAergic cells impairs inhibitory synapse connectivity, synaptic inhibition and cognitive function. Nat Commun. 2016 Nov 9;7:13340. doi: 10.1038/ncomms13340.

Open source paper.

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