April 12, 2024

Claire Story

11th Grade

Dominican Academy

The SYNGAP1 gene, located on chromosome 6, has recently been discovered to have novel implications. It was originally discovered in 1998 by Richard Huganir, Ph.D., from the Johns Hopkins University School of Medicine and was known for controlling learning and memory in mammals. It was previously thought that the gene solely encoded proteins to regulate the formation of synapses, links between brain cells that strengthen as a person learns something new. Recent experiments have revealed a new function of the SYNGAP1 gene, and this discovery may alter the methods and treatments used for children with SYNGAP1 irregularities.

Having abnormal levels of the SYNGAP1 gene leads to neurological disorders, including autism and epilepsy. According to the National Library of Medicine, those with SYNGAP1 mutations display “severe intellectual disability” in early childhood, experiencing problems with motor and speech proficiencies. Hypotonia, developmental regression, and epilepsy are also common consequences of this neurological disorder. SYNGAP1-related intellectual disorders are the cause of one to two percent of all intellectual disabilities. It is inherited in an autosomal dominant manner and has been previously treated using anti-seizure medications or methods used for Autism Spectrum Disorder (ASD). With the newest discoveries involving the SYNGAP1 gene, researchers hope to find new treatments for these disorders.

Cutting-edge research performed by Johns Hopkins Medicine neuroscientists has confirmed the unknown function of the SYNGAP1 gene. This research was led by neuroscience instructor Yoichi Araki and Richard Huganir, Ph.D., in collaboration with Timothy Gamache, Elizabeth Gerber, Ingie Hong, Richard Johnson, Alfredo Kirkwood, Bian Liu, Kacey Rajkovich, Thanh Hai Tran, and Qianwen Zhu. The team experimented with mice to find that the encoded proteins of SYNGAP1, called SynGAP, can act as scaffolding proteins, allowing it to control synaptic plasticity, which determines the strength of synapses over some time. They found that, when interacting with PSD-95, a major scaffolding protein, SynGAP proteins behave abnormally: they alter their structures and turn into liquid drops. Curious about this physical property, the research team carefully “removed the enzymic function of SynGAP without affecting its structure” (Johns Hopkins Medicine). Even without a particular function, the protein still behaved normally, demonstrating that the structure of the protein is significant, not the enzymatic activity. With this newfound information, there is a possibility for new treatments of SYNGAP1-related intellectual disorders. The researchers concluded that only the basic structure of the SynGAP protein is needed for a person to display normal neurological behavior.

Furthermore, the team found that the SynGAP protein connects to PSD-95 proteins when in a state of rest. It then releases itself during synaptic plasticity, allowing neurotransmitter receptors, such as AMPA receptor/TARP complexes, to bind to PSD-95, strengthening the synapses. According to the team’s research article, the main function of the gene is “ultimately regulating the recruitment of AMPA receptors during plasticity” (Araki). In children with SYNGAP1 abnormalities, about half of the amount of SynGAP proteins are present at synapses. This allows an abundance of neurotransmitters to attach to PSD-95, increasing brain activity and altering synapse connections in ways that can result in conditions, such as epilepsy. Although there are “no curative measures to date” (Jimenez-Gomez), because of the discoveries about SYNGAP1, it is hopeful that scientists will find methods to treat disorders caused by SYNGAP1 mutations.

The SYNGAP1 gene is still a new discovery in the field of medicine, however, the newest findings have immense potential to change how we think about and treat certain neurological disorders. This gene cannot only control what proteins are sent to synapses but can also regulate neurotransmitter receptors that link to PSD-95 and rely on its structure to be functional. With these fascinating findings, it is exciting to see where this new knowledge will lead.