Dr. Katherine Roche, a member of the scientific advisory board at CureGRIN, is a Senior Investigator at the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health in Maryland.

Dr. Roche is broadly interested in understanding the mechanisms that the brain is able to change and adapt to new information, like learning new skills. Since NMDA receptors are important mediators of learning and memory, Dr. Roche has been studying these receptors for over 20 years. Recently, she has focused on exploring how rare variants lead to neurodevelopmental disorders. One area of interest is understanding how variants in the GRIN genes lead to the improper functioning of NMDA receptors.

In order for nerve cells, called neurons, to send messages to each other, they communicate via a synapse, which is a small space between two nerve cells. For NMDA receptors to function properly, they need to be moved to the synapse, where they can perform their function. Abnormal NMDA receptor functioning can arise when the NMDA receptors are not moved to the correct location. Since variants in GRIN2A and GRIN2B genes are responsible for the production of different parts of the NMDA receptor, variants in these genes may produce abnormal NMDA receptors that don’t move to the correct location. If this is the case, this could be the explanation as to why we see reduced NMDA receptor functioning and associated symptoms in some GRIN variants. The question that Dr. Roche and her lab are working to answer is, how do variants in GRIN2A and GRIN2B affect the movement of NMDA receptors to their correct location? This question is important to answer because understanding how a variant contributes to the improper functioning of NMDA receptors is essential to designing potentially suitable therapeutics.

To understand how variants in GRIN genes lead to abnormal movement of NMDA receptors, Dr. Roche’s lab is currently studying two variants of GRIN2A and GRIN2B. So far, they have found that rare variants associated with disorders that affect the movement of NMDA receptors are loss of function variants, leading to not enough NMDA receptors in their correct location at the synapse.

A recent article published in Cell Reports outlines their findings of one of the variants, a GRIN2A variant found in a patient with epilepsy. The main finding was that the variant caused defects in the movement of NMDA receptors. They also found other effects of the variant, including reduced spine density, which is the part of the neuron that receives messages, and decreased activity of the neuron. These effects may be common effects of multiple specific variants that further suggest how the variant may affect the brain. Identifying common effects of many variants is another goal of Dr. Roche’s lab because this may provide insights into therapeutic angles that can be taken toward multiple variants, not just the two specific variants that the lab studies in depth.  

Dr. Roche is excited to see important questions that we still have about GRIN genes and NMDA receptors being tackled on multiple levels by researchers, geneticists, and clinicians. She is looking forward to finding answers to these questions, with the ultimate goal of improving therapeutic development.