The Role of Ionotropic Glutamate Receptors in Childhood Neurodevelopmental Disorders: Autism Spectrum Disorders and Fragile X Syndrome

Abstract

Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are relatively common childhood neurodevelopmental disorders with increasing incidence in recent years. They are currently accepted as disorders of the synapse with alterations in different forms of synaptic communication and neuronal network connectivity. The major excitatory neurotransmitter system in brain, the glutamatergic system, is implicated in learning and memory, synaptic plasticity, neuronal development. While much attention is attributed to the role of metabotropic glutamate receptors in ASD and FXS, studies indicate that the ionotropic glutamate receptors (iGluRs) and their regulatory proteins are also altered in several brain regions. Role of iGluRs in the neurobiology of ASD and FXS is supported by a weight of evidence that ranges from human genetics to in vitro cultured neurons. In this review we will discuss clinical, molecular, cellular and functional changes in NMDA, AMPA and kainate receptors and the synaptic proteins that regulate them in the context of ASD and FXS. We will also discuss the significance for the development of translational biomarkers and treatments for the core symptoms of ASD and FXS.

NMDA receptor‐deficient mice display sexual dimorphism in the onset and severity of behavioural abnormalities

“…It is not clear whether schizophrenia and autism represent opposite ends of the spectrum (Crespi & Badcock ), or are instead disorders with shared neurological features (Grant ; Penzes et al ; Stefansson et al ). With the important caveat that both of these disorders are multigenic and multifactorial, molecular studies suggest that susceptibility genes for both of these disorders negatively impact NMDAR levels or signalling (Fromer et al ; Maclaren et al ; Stefansson et al ; Uzunova et al ). For these reasons, our findings can be informative for the understanding of both of these disorders.…”

Structural Bases of Desensitization in AMPA Receptor-Auxiliary Subunit Complexes

“…The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) functions on the millisecond timescale and serves as an indicator of synaptic strength. Aberrancies in AMPAR function lead to a broad range of neurodegenerative disorders, from Alzheimer’s to Parkinson’s diseases (Bowie, 2008; Traynelis et al, 2010), schizophrenia, epilepsy (Rogawski, 2013), ischemia-induced trauma (Lo et al, 2003; Oguro et al, 1999) and fragile-X syndrome (Uzunova et al, 2014). …”

Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops

“…Reviews of ASD that categorize genes according to properties of the proteins they encode, such as their anatomical location (Ebert and Greenberg, 2013; Toro et al, 2010; Uzunova et al, 2014), their protein-protein interactions with other gene products (Sakai et al, 2011), or their transcript levels in correlation with other mRNAs (Voineagu et al, 2011). Each provides valuable groupings of proteins, but not an explicit hypothesis about their mechanistic relationship to the disorder as a whole.…”