Anti-NMDA receptor encephalitis: a review of mechanistic studies.

NMDA receptors (NMDARs) are ion channels gated by glutamate, the major excitatory neurotransmitter in the central nervous system. Anti-NMDA receptor (anti-NMDAR) encephalitis is an autoimmune disease characterized by the presence of autoantibodies against the NMDAR GluN1 subunit. Here we briefly review current advances in the understanding of the mechanisms underlying the pathogenesis of anti-NMDAR encephalitis. The autoantibodies bind to and cross-link the endogenous NMDARs, disrupt the interaction of NMDARs with receptor tyrosine kinase EphB2 leading to internalization and reduced function of NMDARs. Hypofunction of the NMDARs results in impairment in long-term potentiation and deficit in learning and memory, leads to development of depression-like behavior, and lowers the threshold for seizures. Recent development of active immunization models of anti-NMDAR encephalitis provides insight into the inflammation process and paves the way for further studies that may lead to better treatment.

Dopamine D1 receptor-mediated NMDA receptor insertion depends on Fyn but not Src kinase pathway in prefrontal cortical neurons.

BACKGROUND: Interactions between dopamine and glutamate in the prefrontal cortex are essential for cognitive functions such as working memory. Modulation of N-methyl-D-aspartic acid (NMDA) receptor functions by dopamine D1 receptor is believed to play a critical role in these functions. The aim of the work reported here is to explore the signaling pathway underlying D1 receptor-mediated trafficking of NMDA receptors in cultured rat prefrontal cortical neurons. RESULTS: Activation of D1 receptor by selective agonist SKF-81297 significantly increased the expression of NR2B subunits. This effect was completely blocked by small interfering RNA knockdown of Fyn, but not Src. Under control conditions, neither Fyn nor Src knockdown exhibited significant effect on basal NR2B expression. D1 stimulation significantly enhanced NR2B insertion into plasma membrane in cultured PFC neurons, a process obstructed by Fyn, but not Src, knockdown. CONCLUSIONS: Dopamine D1 receptor-mediated increase of NMDA receptors is thus Fyn kinase dependent. Targeting this signaling pathway may be useful in treating drug addiction and schizophrenia.

Dopamine D(1) receptor-mediated enhancement of NMDA receptor trafficking requires rapid PKC-dependent synaptic insertion in the prefrontal neurons.

Understanding the interaction between dopamine and glutamate, particularly the interaction of dopamine and NMDA receptors, may enable a more rational approach to the treatment of schizophrenia, drug addiction, and other psychiatric disorders. We show that, in prefrontal cortical neurons, dopamine D(1)-induced enhancement of NMDA receptor function depends on rapid insertion of new NMDA receptor 2B subunits on the synaptic surface. Protein kinase A (PKA) inhibitor, but not protein kinase C (PKC) inhibitor, completely blocked dopamine D(1) agonist SKF-81297-induced increase of the total expression of NMDA receptors. Furthermore, SKF-81297 failed to alter the surface expression and synaptic insertion of NMDA receptors in the presence of PKA inhibitor, phospholipase C inhibitor, PKC inhibitor, or Src family kinase inhibitor. Our data suggest that D(1)-mediated enhancement of NMDA current depends on the NMDA receptor trafficking through rapid synaptic insertion and both PKA and PKC signaling pathways play important roles in the regulatory process. Although both PKA and PKC mediate the D(1)-induced enhancement of NMDA receptors, the phospholipase C-PKC-Src pathway is only required for surface expression and new synaptic insertion of NMDA receptors.

Activation of glycogen synthase kinase-3 beta is required for hyperdopamine and D2 receptor-mediated inhibition of synaptic NMDA receptor function in the rat prefrontal cortex.

The interactions between dopamine and glutamate systems play an essential role in normal brain functions and neuropsychiatric disorders. The mechanism of NMDA receptor regulation through high concentrations of dopamine, however, remains unclear. Here, we show the signaling pathways involved in hyperdopaminergic regulation of NMDA receptor functions in the prefrontal cortex by incubating cortical slices with high concentration of dopamine or administering dopamine reuptake inhibitor 1-(2-[bis-(4-fluorophenyl)methoxy]ethyl)- 4-(3-phenylpropyl)piperazine (GBR12909) in vivo. We found that, under both conditions, the synaptic NMDA receptor-mediated currents were significantly attenuated by excessive dopamine stimulation through activation of D(2) receptors. Furthermore, high dose of dopamine failed to affect NMDA receptor-mediated currents after blockade of NR2B subunits but triggered a dynamin-dependent endocytosis of NMDA receptors. The high-dose dopamine/D(2) receptor-mediated suppression of NMDA receptors was involved in the increase of glycogen synthase kinase-3beta (GSK-3beta) activity, which in turn phosphorylates beta-catenin and disrupts beta-catenin-NR2B interaction, but was dependent on neither Gq11 nor PLC (phospholipase C). Moreover, the hyperdopamine induced by GBR12909 significantly decreased the expression of both surface and intracellular NR2B proteins, as well as NR2B mRNA levels, suggesting an inhibition of protein synthesis. These effects were, however, completely reversed by administration of either GSK-3beta inhibitor or D(2) receptor antagonist. These results therefore suggest that GSK-3beta is required for the hyperdopamine/D(2) receptor-mediated inhibition of NMDA receptors in the prefrontal neurons and these actions may underlie D(2) receptor-mediated psychostimulant effects and hyperdopamine-dependent behaviors in the brain.

NMDA receptors are movin' in.

Dynamic modulation of the number of postsynaptic glutamate receptors is considered one of the main mechanisms for altering the strength of excitatory synapses in the central nervous system (CNS). However, until recently N-methyl-d-aspartate (NMDA) receptors were considered relatively stable once in the plasma membrane, especially in comparison with alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors that are internalized at a high rate. A series of recent studies has changed this viewpoint by revealing that NMDA receptors are subject to constitutive as well as agonist-induced internalization through clathrin-mediated endocytosis. Surprisingly, agonist-induced internalization is not dependent on current flow through the NMDA channel, and the receptors are primed for this type of internalization by selective stimulation of the glycine site but not of the glutamate site. Endocytosis of NMDA receptors provides a fundamental mechanism for dynamic regulation of the number of NMDA receptors at synapses, which might be important for physiological and pathological functioning of the CNS.

Unique domain anchoring of Src to synaptic NMDA receptors via the mitochondrial protein NADH dehydrogenase subunit 2.

Src is the prototypic protein tyrosine kinase and is critical for controlling diverse cellular functions. Regions in Src define structural and functional domains conserved in many cell signaling proteins. Src also contains a region of low sequence conservation termed the unique domain, the function of which has until now remained enigmatic. Here, we show that the unique domain of Src is a protein-protein interaction region and we identify NADH dehydrogenase subunit 2 (ND2) as a Src unique domain-interacting protein. ND2 is a subunit of complex I in mitochondria, but we find that ND2 interacts with Src outside this organelle at excitatory synapses in the brain. ND2 acts as an adapter protein anchoring Src to the N-methyl-d-aspartate (NMDA) receptor complex, and is crucial for Src regulation of synaptic NMDA receptor activity. By showing an extramitochondrial action for a protein encoded in the mitochondrial genome, we identify a previously unsuspected means by which mitochondria regulate cellular function, suggesting a new paradigm that may be of general relevance for control of Src signaling.

Glycine binding primes NMDA receptor internalization.

NMDA (N-methyl-d-aspartate) receptors (NMDARs) are a principal subtype of excitatory ligand-gated ion channel with prominent roles in physiological and disease processes in the central nervous system. Recognition that glycine potentiates NMDAR-mediated currents as well as being a requisite co-agonist of the NMDAR subtype of 'glutamate' receptor profoundly changed our understanding of chemical synaptic communication in the central nervous system. The binding of both glycine and glutamate is necessary to cause opening of the NMDAR conductance pore. Although binding of either agonist alone is insufficient to cause current flow through the channel, we report here that stimulation of the glycine site initiates signalling through the NMDAR complex, priming the receptors for clathrin-dependent endocytosis. Glycine binding alone does not cause the receptor to be endocytosed; this requires both glycine and glutamate site activation of NMDARs. The priming effect of glycine is mimicked by the NMDAR glycine site agonist d-serine, and is blocked by competitive glycine site antagonists. Synaptic as well as extrasynaptic NMDARs are primed for internalization by glycine site stimulation. Our results demonstrate transmembrane signal transduction through activating the glycine site of NMDARs, and elucidate a model for modulating cell-cell communication in the central nervous system.