scholarly journals Alteration of NMDA receptor trafficking as a cellular hallmark of psychosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Agnès Espana ◽  
Henrik Seth ◽  
Julie Jézéquel ◽  
Tingting Huang ◽  
Delphine Bouchet ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Membrane Trafficking ◽  
Hippocampal Neurons ◽  
Psychotic Disorders ◽  
Acoustic Startle ◽  
Acoustic Startle Reflex ◽  
Surface Dynamics ◽  
Genetic Manipulations ◽  
Biological Substrate ◽  
Developing Rat

AbstractA dysfunction of the glutamatergic transmission, especially of the NMDA receptor (NMDAR), constitutes one of the main biological substrate of psychotic disorders, such as schizophrenia. The NMDAR signaling hypofunction, through genetic and/or environmental insults, would cause a neurodevelopmental myriad of molecular, cellular, and network alterations that persist throughout life. Yet, the mechanisms underpinning NMDAR dysfunctions remain elusive. Here, we compared the membrane trafficking of NMDAR in three gold-standard models of schizophrenia, i.e., patient’s cerebrospinal fluids, genetic manipulations of susceptibility genes, and prenatal developmental alterations. Using a combination of single nanoparticle tracking, electrophysiological, biochemical, and behavioral approaches in rodents, we identified that the NMDAR trafficking in hippocampal neurons was consistently altered in all these different models. Artificial manipulations of the NMDAR surface dynamics with competing ligands or antibody-induced receptor cross-link in the developing rat brain were sufficient to regulate the adult acoustic startle reflex and compensate for an early pathological challenge. Collectively, we show that the NMDAR trafficking is markedly altered in all clinically relevant models of psychosis, opening new avenues of therapeutical strategies.

scholarly journals Septin 9 interacts with kinesin KIF17 and interferes with the mechanism of NMDA receptor cargo binding and transport

2016 ◽  
Vol 27 (6) ◽  
pp. 897-906 ◽  
Author(s):  
Xiaobo Bai ◽  
Eva P. Karasmanis ◽  
Elias T. Spiliotis
Keyword(s):  
Nmda Receptor ◽  
Hippocampal Neurons ◽  
Intracellular Transport ◽  
Tail Domain ◽  
Septin 9 ◽  
Microtubule Motor ◽  
Underlying Mechanisms ◽  
Dependent Transport ◽  
Developing Rat ◽  
Cargo Binding

Intracellular transport involves the regulation of microtubule motor interactions with cargo, but the underlying mechanisms are not well understood. Septins are membrane- and microtubule-binding proteins that assemble into filamentous, scaffold-like structures. Septins are implicated in microtubule-dependent transport, but their roles are unknown. Here we describe a novel interaction between KIF17, a kinesin 2 family motor, and septin 9 (SEPT9). We show that SEPT9 associates directly with the C-terminal tail of KIF17 and interacts preferentially with the extended cargo-binding conformation of KIF17. In developing rat hippocampal neurons, SEPT9 partially colocalizes and comigrates with KIF17. We show that SEPT9 interacts with the KIF17 tail domain that associates with mLin-10/Mint1, a cargo adaptor/scaffold protein, which underlies the mechanism of KIF17 binding to the NMDA receptor subunit 2B (NR2B). Significantly, SEPT9 interferes with binding of the PDZ1 domain of mLin-10/Mint1 to KIF17 and thereby down-regulates NR2B transport into the dendrites of hippocampal neurons. Measurements of KIF17 motility in live neurons show that SEPT9 does not affect the microtubule-dependent motility of KIF17. These results provide the first evidence of an interaction between septins and a nonmitotic kinesin and suggest that SEPT9 modulates the interactions of KIF17 with membrane cargo.

Long-term NMDA receptor inhibition affects NMDA receptor expression and alters glutamatergic activity in developing rat hippocampal neurons

Toxicology ◽  
2015 ◽  
Vol 333 ◽  
pp. 147-155 ◽  
Author(s):  
Barbara Sinner ◽  
Oliver Friedrich ◽  
Regina Lindner ◽  
Anika Bundscherer ◽  
Bernhard M. Graf
Keyword(s):  
Nmda Receptor ◽  
Hippocampal Neurons ◽  
Receptor Expression ◽  
Receptor Inhibition ◽  
Developing Rat

Modulation of the acoustic startle reflex by emotionally-toned filmclips

1996 ◽  
Author(s):  
Hossein Kaviani ◽  
Jeffrey A. Gray ◽  
Stuart A. Checkley ◽  
Veena Kumari ◽  
Philip J. Corr ◽  
...  
Keyword(s):  
Acoustic Startle ◽  
Startle Reflex ◽  
Acoustic Startle Reflex

Fast NMDA Receptor–Mediated Synaptic Currents in Neurons From Mice Lacking the ε2 (NR2B) Subunit

2000 ◽  
Vol 83 (1) ◽  
pp. 616-620 ◽  
Author(s):  
Kenneth R. Tovar ◽  
Kathleen Sprouffske ◽  
Gary L. Westbrook
Keyword(s):  
Nmda Receptor ◽  
Hippocampal Neurons ◽  
Postsynaptic Membrane ◽  
Synaptic Activity ◽  
Wild Type ◽  
Nmda Receptor Subunit ◽  
Deactivation Kinetics ◽  
Low Concentrations ◽  
Specific Antagonist

The N-methyl-d-aspartate (NMDA) receptor has been implicated in the formation of synaptic connections. To investigate the role of the ε2 (NR2B) NMDA receptor subunit, which is prominently expressed during early development, we used neurons from mice lacking this subunit. Although ε2−/− mice die soon after birth, we examined whether NMDA receptor targeting to the postsynaptic membrane was dependent on the ε2 subunit by rescuing hippocampal neurons from these mice and studying them in autaptic cultures. In voltage-clamp recordings, excitatory postsynaptic currents (EPSCs) from ε2−/− neurons expressed an NMDA receptor–mediated EPSC that was apparent as soon as synaptic activity developed. However, compared with wild-type neurons, NMDA receptor–mediated EPSC deactivation kinetics were much faster and were less sensitive to glycine, but were blocked by Mg2+ or AP5. Whole cell currents from ε2−/− neurons were also more sensitive to block by low concentrations of Zn2+ and much less sensitive to the ε2-specific antagonist ifenprodil than wild-type currents. The rapid NMDA receptor–mediated EPSC deactivation kinetics and the pharmacological profile from ε2−/−neurons are consistent with the expression of ζ1/ε1 diheteromeric receptors in excitatory hippocampal neurons from mice lacking the ε2 subunit. Thus ε1 can substitute for the ε2 subunit at synapses and ε2 is not required for targeting of NMDA receptors to the postsynaptic membrane.

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