Researchers at The University of Queensland (UQ), working to gain a better understanding of how brain cells work, say they have discovered the underlying mechanism of a rare genetic mutation that can cause epilepsy. The team published its study (“Regulation of NMDA receptor trafficking and gating by activity-dependent CaMKIIa phosphorylation of the GluN2A subunit”) in Cell Reports.
“NMDA receptor (NMDAR)-dependent Ca2+ influx underpins multiple forms of synaptic plasticity. Most synaptic NMDAR currents in the adult forebrain are mediated by GluN2A-containing receptors, which are rapidly inserted into synapses during long-term potentiation (LTP); however, the underlying molecular mechanisms remain poorly understood,” write the investigators.
“In this study, we show that GluN2A is phosphorylated at Ser-1459 by Ca2+/calmodulin-dependent kinase IIa (CaMKIIa) in response to glycine stimulation that mimics LTP in primary neurons. Phosphorylation of Ser-1459 promotes GluN2A interaction with the sorting nexin 27 (SNX27)-retromer complex, thereby enhancing the endosomal recycling of NMDARs.
“Loss of SNX27 or CaMKIIa function blocks the glycine-induced increase in GluN2A-NMDARs on the neuronal membrane. Interestingly, mutations of Ser-1459, including the rare S1459G human epilepsy variant, prolong the decay times of NMDAR-mediated synaptic currents in heterosynapses by increasing the duration of channel opening.
“These findings not only identify a critical role of Ser-1459 phosphorylation in regulating the function of NMDARs, but they also explain how the S1459G variant dysregulates NMDAR function.”
Victor Anggono, PhD, from UQ’s Queensland Brain Institute, reported that his team made the findings while researching nerve cell communications, which are an important process in normal brain function.
“We’re both excited and astounded to make such an important contribution to the field of cellular and molecular neuroscience,” Anggono said, stressing that the mutation was extremely rare, with only one reported case in the world to date.
His team studies receptors, that are attached to cell surfaces, that led to the discovery.
“It turns out that this particular mutation causes receptors in brain cells to behave differently, resulting in an imbalance in brain cell communication, and that can lead to disorders,” continued Anggono.
“For example, cells that talk too much are associated with epilepsy and unwanted cell death, while cells that talk too little have negative impacts on learning and memory. There are also many examples of other mutations in the same gene that are known to be associated with epilepsy.
“What we know is that this receptor is critical for brain function and can lead to epilepsy when its function is misregulated. The findings point the way for further research to understand and potentially treat similar mutations.”
The imbalance in brain cell communications is also believed to be involved in neurological conditions, including Alzheimer’s disease and autism spectrum disorders. Anggono said the research provided a springboard for developing personalized medicines to target the mutation.
“Receptor blockers, which have been approved by the FDA, are already available for human treatment, but the challenge is to find the right ones and see how patients respond,” he pointed out.