Biology subjects

Yong, X. L. H.

Publications and source records attributed to Yong, X. L. H..

3 recordsLinked to original sources

bioRxiv2025

Tau controls NMDA receptor trafficking during homeostatic synaptic plasticity

Homeostatic synaptic plasticity is essential for maintaining stable neural circuit function by preventing excessive neuronal excitation or inhibition. Chronic perturbation of neuronal activity triggers a compensatory modulation of the number of -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors at the excitatory synapses. Previous research has primarily focused on AMPA receptors, yet the molecular mechanisms regulating the trafficking of NMDA receptors during homeostatic synaptic scaling remain unclear. Here we identify the microtubule-associated protein Tau as an essential molecule that mediates the synaptic upscaling of GluN2B-containing NMDA receptors during prolonged synaptic inactivity. Chronic activity blockade increases Tau phosphorylation at Ser-235 by cyclin-dependent kinase 5 (Cdk5), enhancing its interaction with and retention of active Fyn tyrosine kinase in the postsynaptic compartment. This promotes the phosphorylation of GluN2B at Tyr-1472, subsequently stabilising the expression of NMDA receptors on the neuronal plasma membrane. Finally, we showed that Tau pathology and disease-associated mutations in Tau and the GluN2B carboxyl-terminal tail disrupt the homeostatic synaptic upscaling of NMDA receptors following chronic neuronal silencing. Together, our findings identify a physiological role for Tau in homeostatic synaptic plasticity, the perturbation of which can lead to neuronal hyperexcitation, seizures and excitotoxic cell death.

neuroscience↗

bioRxiv2024

Saturated fatty acid-Coenzyme A supplementation restores neuronal energy levels and protein homeostasis in hereditary spastic paraplegia

Mitochondrial ATP production is fuelled by a fatty acid flux generated by phospholipase and triglyceride lipases in metabolically demanding tissues such as heart and liver, while the brain has long been believed to use almost solely glucose for energy. Phospholipase A1 enzyme DDHD2 is a major triglyceride lipase in the brain, and the loss of DDHD2 function results in a saturated free fatty acid (sFFA) imbalance and lipid droplet (LD) accumulation in the brain. The LD accumulation in neurons has been enigmatic as LDs are mainly considered to serve as a fuel storage. Here, we demonstrate that the loss of DDHD2 results in a mitochondrial respiratory dysfunction that leads to a significant decrease in ATP production and acetyl coenzyme A levels in neurons, even when the glycolytic breakdown of glycose occurs normally. Loss of DDHD2 also leads to a presynaptic defect as well as an imbalance in the global protein homeostasis in the neurons. These defects were rescued by external supplementation of the sFFA myristic acid coupled with its cofactor coenzyme A (Myr-CoA), indicating sFFA fuelling for neuronal {beta}-oxidation. We have thus discovered that the sFFAs released by the activity of DDHD2 play a central role in providing energy to fuel synaptic function. One Sentence SummaryFree fatty acids released by DDHD2 activity play a central role in maintaining neuronal energy levels and synaptic function.

neuroscience↗

bioRxiv2021

Regulation of NMDA receptor trafficking and gating by activity-dependent CaMKIIα phosphorylation of the GluN2A subunit

NMDAR-dependent Ca2+ influx underpins multiple forms of synaptic plasticity. In the adult forebrain, the majority of synaptic NMDAR currents are mediated by GluN2A-containing NMDARs. These receptors are rapidly inserted into synapses during LTP; however, the underlying molecular mechanisms remain poorly understood. Here we show that GluN2A is phosphorylated at Ser-1459 by CaMKII in response to glycine stimulation that mimics LTP in primary neurons. Phosphorylation of Ser-1459 promotes GluN2A interaction with the SNX27-retromer complex, therefore enhancing the endosomal recycling of NMDARs. Loss of SNX27 or CaMKII 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 decay times of NMDAR-mediated synaptic currents in heterosynapses by increasing the active duration of channel openings. Taken together, these findings not only identify a critical role of Ser-1459 phosphorylation in regulating the function of NMDARs, but also explain how the S1459G epilepsy variant dysregulates NMDAR function.

neuroscience↗