Alteration of NMDA receptor trafficking as a cellular hallmark of psychosis

Agnès Espana,Eric Hanse,Marylin Lepleux,Tingting Huang,Marion Schneider,Julie Jézéquel,Laurent Groc,Karl Bechter,Henrik Seth,Hélène Gréa,Delphine Bouchet

doi:10.1038/s41398-021-01549-7

Abstract

A 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.

Highlights

Psychotic disorders, such as schizophrenic spectrum disorders (SCZSD) [1], are life-threatening mental illnesses that impose a substantial burden of morbidity and mortality
Cerebrospinal fluid (CSF) from patients with SCZSD alter N-methyl-D-aspartate receptor (NMDAR) surface dynamics and organization In order to test the hypothesis that the CSF of patients suffering from SCZSD can alter the organization and function of NMDAR located at the plasma membrane of neurons, we performed a single nanoparticle tracking experiment in cultured hippocampal neurons
We unveil that NMDAR surface dynamics is consistently impaired in genetic and developmental models of psychosis

Summary

Introduction

Psychotic disorders, such as schizophrenic spectrum disorders (SCZSD) [1], are life-threatening mental illnesses that impose a substantial burden of morbidity and mortality. Cells were acutely exposed to CSF collected from patients with various neurological, inflammatory, and psychiatric conditions (Fig. 1a), and the membrane dynamics of synaptic NMDAR were recorded (see “Methods” section). C The area of GluN1-NMDAR surface clusters were significantly reduced by SCZSD CSF (Control, n = 103 clusters; SCZSD, n = 99; SAH, n = 116; N = 6–8 neurons per condition; ***p < 0.001, ANOVA 1 followed by Newman–Keuls multiple comparisons test).

Results

Conclusion