Abstract
BackgroundN-methyl-D-aspartate receptor (NMDAR) hypofunction has been proposed to underlie the pathogenesis of schizophrenia. Specifically, reduced function of NMDARs leads to altered balance between excitation and inhibition which further drives neural network malfunctions. Clinical studies suggested that NMDAR modulators (glycine, D-serine, D-cycloserine and glycine transporter inhibitors) may be beneficial in treating schizophrenia patients. Preclinical evidence also suggested that these NMDAR modulators may enhance synaptic NMDAR function and synaptic plasticity in brain slices. However, an important issue that has not been addressed is whether these NMDAR modulators modulate neural activity/spiking in vivo.MethodsBy using in vivo calcium imaging and single unit recording, we tested the effect of D-cycloserine, sarcosine (glycine transporter 1 inhibitor) and glycine, on schizophrenia-like model mice.ResultsIn vivo neural activity is significantly higher in the schizophrenia-like model mice, compared to control mice. D-cycloserine and sarcosine showed no significant effect on neural activity in the schizophrenia-like model mice. Glycine induced a large reduction in movement in home cage and reduced in vivo brain activity in control mice which prevented further analysis of its effect in schizophrenia-like model mice.ConclusionsWe conclude that there is no significant impact of the tested NMDAR modulators on neural spiking in the schizophrenia-like model mice.
Highlights
N-methyl-D-aspartate receptor (NMDAR) hypofunction has been proposed to underlie the pathogenesis of schizophrenia
MK-801 To obtain in vivo Ca2+ signals, virus coding GCaMP6s was injected into mouse frontal association cortex (FrA)
We focused on the Ca2+ responses in the somata of layer II/III FrA neurons since FrA has significant relevance to schizophrenia pathology and is more accessible for in vivo two photon imaging than medial prefrontal cortex [53, 54] (Fig. 1a)
Summary
N-methyl-D-aspartate receptor (NMDAR) hypofunction has been proposed to underlie the pathogenesis of schizophrenia. The glutamate hypofunction model of schizophrenia proposes that reduced function of glutamate receptors, especially NMDA subtypes on the inhibitory neurons leads to an imbalanced excitation and inhibition, and results in altered neural network functions (such as oscillations and working memory) [1,2,3,4]. These altered functions are proposed to drive the pathogenesis of schizophrenia and are likely contribute to on-going schizophrenia pathology. In addition to directly administering NMDAR co-agonists, another widely pursued approach is to elevate the endogenous glycine level by blocking its uptake using selective glycine transporter inhibitors, such as glycine
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