Amy J. Gleichman

Anti–N-Methyl-D-Aspartate Receptor (NMDAR) Encephalitis in Children and Adolescents

To report the clinical features of anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis in patients ≤ 18 years old.

Fyn-mediated Phosphorylation of NR2B Tyr-1336 Controls Calpain-mediated NR2B Cleavage in Neurons and Heterologous Systems

Cleavage of the intracellular carboxyl terminus of the N-methyl-d-aspartate (NMDA) receptor 2 subunit (NR2) by calpain regulates NMDA receptor function and localization. Here, we show that Fyn-mediated phosphorylation of NR2B controls calpain-mediated NR2B cleavage. In cultured neurons, calpain-mediated NR2B cleavage is significantly attenuated by blocking NR2B phosphorylation of Tyr-1336, but not Tyr-1472, via inhibition of Src family kinase activity or decreasing Fyn levels by small interfering RNA. In HEK cells, mutation of Tyr-1336 eliminates the potentiating effect of Fyn on calpain-mediated NR2B cleavage. The potentiation of NR2B cleavage by Fyn is limited to cell surface receptors and is associated with calpain translocation to plasma membranes during NMDA receptor activation. Finally, reducing full-length NR2B by calpain does not decrease extrasynaptic NMDA receptor function, and truncated NR1/2B receptors similar to those generated by calpain have electrophysiological properties matching those of wild-type receptors. Thus, the Fyn-controlled regulation of NMDA receptor cleavage by calpain may play critical roles in controlling NMDA receptor properties during synaptic plasticity and excitotoxicity.

Astrocytic therapies for neuronal repair in stroke.

Stroke is a leading cause of disability and death worldwide. Much of the work on improving stroke recovery has focused on preventing neuronal loss; however, these approaches have repeatedly failed in clinical trials. Conversely, relatively little is known about the mechanisms of repair and recovery after stroke. Stroke causes an initial process of local scar formation that confines the damage, and a later and limited process of tissue repair that involves the formation of new connections and new blood vessels. Astrocytes are central to both scar formation and to tissue repair after stroke. Astrocytes regulate the synapses and blood vessels within their cellular projections, or domain, and both respond to and release neuroimmune molecules in response to damage. Despite this central role in brain function, astrocytes have been largely neglected in the pursuit of effective stroke therapeutics. Here, we will review the changes astrocytes undergo in response to stroke, both beneficial and detrimental, and discuss possible points of intervention to promote recovery.

NMDA receptor modulation by the neuropeptide apelin: implications for excitotoxic injury

J. Neurochem. (2011) 118, 1113–1123.

Antigenic and mechanistic characterization of anti-AMPA receptor encephalitis.

Anti‐AMPAR encephalitis is a recently discovered disorder characterized by the presence of antibodies in serum or cerebrospinal fluid against the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor. Here, we examine the antigenic specificity of anti‐AMPAR antibodies, screen for new patients, and evaluate functional effects of antibody treatment of neurons.

Picking Up the Pieces: The Roles of Functional Remnants of Calpain-Mediated Proteolysis

Calpain-mediated cleavage of neuronal targets has long been associated with excitotoxicity and synaptic plasticity. In this issue of Neuron, two papers by Xu et al. and Abe and Takeichi explore the respective roles of mGluR1alpha cleavage in excitotoxicity and beta-catenin cleavage in transcriptional control. Together, these papers show the functional importance of fragments of calpain-mediated cleavage.

Anti-NMDA Receptor Encephalitis: Clinical Features and Basic Mechanisms

In slightly more than 10 years, anti-NMDA receptor (NMDAR) encephalitis has changed from a rare paraneoplastic syndrome to the most common cause of nonviral encephalitis. It presents fulminantly with progressive psychosis, seizures, and autonomic dysfunction, leading to death if untreated. However, rapid recognition and treatment can lead to survival and a return to baseline levels of functioning in many patients. While initially associated with ovarian teratomas, it is now associated with other tumors and can reflect a postviral event. The antibodies to the NMDAR made in this syndrome are pathogenic and are directed at the extracellular domain of the GluN1 subunit. Such antibodies lead to internalization of NMDARs in model systems, leading to a physiological state characterized by NMDAR hypofunction. Analogous disorders, characterized by antibodies to other synaptic receptors, present with neurological and psychiatric dysfunction and also appear to reflect antibody-induced internalization of receptors. However, this simple pathophysiology may be too simplistic to reflect the complexity of events in anti-NMDAR encephalitis. Future scientific investigations may allow a more complete understanding of this disorder and improve treatment of anti-NMDAR encephalitis.