Multi-Scale Understanding of NMDA Receptor Function in Schizophrenia.

Jo Soo Hyun,Akiko Hayashi-Takagi,Takafumi Inoue

doi:10.3390/biom10081172

Abstract

Schizophrenia is a chronic and disabling psychiatric disorder characterized by disturbances of thought, cognition, and behavior. Despite massive research efforts to date, the etiology and pathophysiology of schizophrenia remain largely unknown. The difficulty of brain research is largely a result of complex interactions between contributory factors at different scales: susceptible gene variants (molecular scale), synaptopathies (synaptic, dendritic, and cell scales), and alterations in neuronal circuits (circuit scale), which together result in behavioral manifestations (individual scale). It is likely that each scale affects the others, from the microscale to the mesoscale to the macroscale, and vice versa. Thus, to consider the intricate complexity of schizophrenia across multiple layers, we introduce a multi-scale, hierarchical view of the nature of this disorder, focusing especially on N-methyl-D-aspartate-type glutamate receptors (NMDARs). The reason for placing emphasis on NMDAR is its clinical relevance to schizophrenia, as well as its diverse functions in neurons, including the robust supralinear synaptic integration provided by N-methyl-D-aspartate-type glutamate (NMDA) spikes and the Ca2+ permeability of the NMDAR, which facilitates synaptic plasticity via various calcium-dependent proteins. Here, we review recent evidence implicating NMDARs in the pathophysiology of schizophrenia from the multi-scale perspective. We also discuss recent advances from optical techniques, which provide a powerful tool for uncovering the mechanisms of NMDAR synaptic pathology and their relationships, with subsequent behavioral manifestations.

Highlights

Schizophrenia is a chronic and devastating mental illness
In light of the accumulating evidence mentioned below, we will focus on the multi-scale aspect of N-methy1-d-aspartate receptor (NMDAR) signaling as a potential contributing factor for schizophrenia
Multiple studies have concluded that schizophrenia can, at least in part, be considered as an NMDAR disorder

Summary

Introduction

Despite rapid advancements in various state-of-the-art technologies, neuroscience still cannot provide a curative treatment for schizophrenia, largely because of a lack of precise understanding of the pathophysiology of the disorder. This is primarily due to the challenge of bridging the large-scale gap, i.e., the gap between the nano- and micro-scales, where chemical and molecular principles govern, and the much larger macroscale of the symptomatic phenomena we wish to understand (Figure 1). Due to the inaccessibility to the living human brain at synaptic resolution, the detailed biological alterations of NMDARs across multiples scales remain almost entirely unknown. We will discuss tools for multi-scale investigation, including animal models and newly developed optogenetic techniques

Functions of NMDAR Signaling

Findings

Evidence of NMDAR Dysregulation from Clinical Studies of Schizophrenia