Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants.

Excitotoxicity induced by NMDA receptors (NMDARs) is thought to be intimately linked to high intracellular calcium load. Unexpectedly, NMDAR-mediated toxicity can be eliminated without affecting NMDAR-induced calcium signals. Instead, excitotoxicity requires physical coupling of NMDARs to TRPM4.

Nasally delivered VEGFD mimetics mitigate stroke-induced dendrite loss and brain damage.

In the adult brain, vascular endothelial growth factor D (VEGFD) is required for structural integrity of dendrites and cognitive abilities. Alterations of dendritic architectures are hallmarks of many neurologic disorders, including stroke-induced damage caused by toxic extrasynaptic NMDA receptor (eNMDAR) signaling. Here we show that stimulation of eNMDARs causes a rapid shutoff of expression, leading to a dramatic loss of dendritic structures.

A microRNA signature of toxic extrasynaptic N-methyl-D-aspartate (NMDA) receptor signaling.

The cellular consequences of N-Methyl-D-Aspartate receptor (NMDAR) stimulation depend on the receptors' subcellular localization. Synaptic NMDARs promote plasticity and survival whereas extrasynaptic NMDARs mediate excitotoxicity and contribute to cell death in neurodegenerative diseases. The mechanisms that couple activation of extrasynaptic NMDARs to cell death remain incompletely understood.

Post-injury Nose-to-Brain Delivery of Activin A and SerpinB2 Reduces Brain Damage in a Mouse Stroke Model.

Synaptic NMDA receptors activating nuclear calcium-driven adaptogenomics control a potent body-own neuroprotective mechanism, referred to as acquired neuroprotection. Viral vector-mediated gene transfer in conjunction with stereotactic surgery has previously demonstrated the proficiency of several nuclear calcium-regulated genes to protect in vivo against brain damage caused by toxic extrasynaptic NMDA receptor signaling following seizures or stroke. Here we used noninvasive nose-to-brain administration of Activin A and SerpinB2, two secreted nuclear calcium-regulated neuroprotectants, for post-injury treatment of brain damage following middle cerebral artery occlusion (MCAO) in C57BL/6N mice.

BDNF Reduces Toxic Extrasynaptic NMDA Receptor Signaling via Synaptic NMDA Receptors and Nuclear-Calcium-Induced Transcription of inhba/Activin A.

The health of neurons is critically dependent on the relative signaling intensities of survival-promoting synaptic and death-inducing extrasynaptic NMDA receptors. Here, we show that BDNF is a regulator of this balance and promotes neuroprotection by reducing toxic NMDA receptor signaling. BDNF acts by initiating synaptic NMDA-receptor/nuclear-calcium-driven adaptogenomics, leading to increased expression of inhibin β-A (inhba).

Nuclear calcium signaling controls methyl-CpG-binding protein 2 (MeCP2) phosphorylation on serine 421 following synaptic activity.

The function of MeCP2, a methylated DNA-interacting protein that may act as a global chromatin modifier, is controlled by its phosphorylation on serine 421. Here we show that in hippocampal neurons, nuclear calcium signaling controls synaptic activity-induced phosphorylation of MeCP2 on serine 421. Pharmacological inhibition of calcium/calmodulin-dependent protein (CaM)kinases blocked activity-induced MeCP2 serine 421 phosphorylation.