SynGAP Research Fund (SRF) Awards $130,000 Grant to Advance Research on Maladaptive Myelination & SYNGAP1-Related Epilepsy – PR16

Posted on:

See official press release here.

Mill Valley, CA – August 2023 – The SynGAP Research Fund 501(c)(3) today announced a $130,000 grant to the Knowles Lab at Stanford University to support research on SynGAP-related intellectual disability (SRID). SRID is a rare neurodevelopmental disorder that causes severe intractable epilepsy, intellectual disability and is one of the leading genetic causes of autism (1,2).

Dr. Juliet Knowles, pediatric neurologist and epileptologist who co-leads the Stanford Medicine Children’s Health Genetic Epilepsy clinic, and her team are  investigating a potential new pathological mechanism and therapeutic target in SYNGAP1 and other progressive forms of pediatric-onset generalized epilepsy: maladaptive myelination. 

Michael Graglia, Managing Director of SRF, says “SYNGAP1 is an ideal candidate for Dr. Knowles’ research given the strong connection with absence epilepsy and the seizure progression we see in our patients.  We are thrilled to support this work and hopeful that the resulting insights will lead to therapies for our patients.”  He continued, “Given Dr. Knowles’ work with PERF and more recently, CURE, we were confident that investing in her lab was an exciting opportunity in research for our community.”

About the Project

Genetic loss of a single copy of SYNGAP1 leads to a progressive condition in children that is characterized by multiple seizure types, including medically refractory absence seizures, difficulties with sleep, cognitive function, and behavioral challenges, which can be profoundly difficult for affected children and their caregivers. Better understanding of the specific causes of disease progression could enhance treatment and quality of life for individuals affected by SYNGAP1. 

While most epilepsy research has focused on the electrical information-transmitting cells of the brain (neurons), Dr. Knowles’s lab was the first to demonstrate that certain supporting cells of the brain, oligodendroglial cells, can also promote epilepsy progression. Oligodendroglia produce myelin, an insulating substance that covers projections (axons) emanating from neurons. In some cases, oligodendroglia can change myelin structure in response to the electrical activity of neurons, a process called activity-dependent myelin plasticity. Axon myelination increases the speed of neuronal impulses and promotes coordination between different regions of the brain. In the healthy state, myelin plasticity aids brain adaptation and learning. However, Dr. Knowles’s lab demonstrated that myelin plasticity can occur in response to typical absence seizures (a milder seizure type with some similarities to the absence seizures that occur in children with SYNGAP1-related epilepsy).

Remarkably, blocking myelin plasticity, either genetically or with a drug, markedly reduced typical absence seizure progression in mice (3). These findings point to myelin plasticity as a new mechanism of epilepsy progression.

The overarching goal of Dr. Knowles’ SRF-supported work is to determine whether myelin plasticity is a tractable therapeutic target to prevent or reduce progression of SYNGAP1-related epilepsy and associated sleep, cognitive and behavioral difficulties.The Knowles Lab will study  oligodendroglial cells and myelination in mice with genetic change in one copy of SYNGAP1, a mouse model that was created by the lab of Dr. Rick Huganir, with support from SRF (4). Dr. Knowles’ lab will determine whether treatment with a drug that blocks myelin plasticity can prevent seizure progression and comorbidities in mice bearing the SYNGAP1 gene variant. 

About SYNGAP1-related intellectual disability (SRID)

SYNGAP1-related intellectual disability (ICD-10 F78.A1) is a rare genetic disorder caused by variants on the SYNGAP1 gene that reduce SynGAP protein levels. This protein acts as a regulator in the synapses (where neurons communicate with each other). When SynGAP protein levels are too low, we see an increase in excitability in the synapses making it difficult for neurons to communicate effectively. This leads to many neurological issues seen in SynGAP patients.

Symptoms of SYNGAP1 include: intellectual disability; epilepsy; hypotonia (low muscle tone); gross and fine motor skill delays; autism spectrum disorder; gastro-intestinal disorders; sleep and behavior disorders and visual abnormalities. 

About the Knowles Lab

The Knowles Lab at Stanford University (  conducts basic, translational and clinical research to study how seizures shape white matter, and how changes in white matter shape the course of epilepsy and its comorbidities. Using innovative imaging, electrophysiological, histological and molecular biology techniques, the Knowles Lab hopes to better understand neuron-glial interactions in epilepsy and to develop treatments that improve the lives of children with epilepsy.

California Synaptopathy Clinic

Dr. Juliet Knowles is also a founder of the newly formed California Synaptopathy Clinic at Stanford, focused on providing expert care for children affected by genetic changes leading to altered synaptic function and epilepsy, such as SYNGAP1 and STXBP1. More information about the California Synaptopathy Clinic can be found here.

About the SynGAP Research Fund  

The mission of the SynGAP Research Fund is to improve the quality of life for SYNGAP1 patients through the research and development of treatments, therapies and support systems. SRF was founded in the US in 2018 as a 501(c)(3) US public charity, and families created sister organizations for SRF in the UK in 2020, in Europe (Netherlands) in 2022, and in Latin America (Colombia) in 2023. Completely family-led, SRF is the largest non-government funders of SynGAP research having committed over $4 million in grants to date. The founders cover all operational costs, ensuring donations fund science. SRF’s grant program awards one or two-year grants to investigators, physician residents, and clinicians who are interested in studying SYNGAP1. SRF grants are intended to help researchers explore novel ideas and answer open questions related to the clinical aspects of and therapies for SRID. SRF is a member of the COMBINEDbrain, Global Genes Foundation Alliance, the Everylife Foundation Community Congress, Personalized Medicine Coalition, Rare Epilepsy Network, and the Epilepsy Leadership Council.

For more on SRF, visit: or follow @cureSYNGAP1

Relevant papers