Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Jan;12(1):71-98.
doi: 10.2174/1570159X113116660046.

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

Affiliations
Free PMC article

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

Genoveva Uzunova et al. Curr Neuropharmacol. .
Free PMC article

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.

Keywords: AMPA receptor; Arc; Fragile X syndrome; GRIP1/2; MAP1B; NMDA receptor.; autism spectrum disorder; kainate receptor; memantine; metabotropic glutamate receptor; neuroligin.

Figures

Fig. (1)
Fig. (1)
Constitutive NMDA-receptor hypofunction causes selective disruption of parvalbumin-expressing (PV+), fast-spiking GABAergic interneurons (FSI). (a) Immunoreactivity for FSI (parvalbumin) is significantly reduced in NR1neo-/- mice. (b) Protein expression for markers of GABA interneuron populations assessed by Western blot. Calbindin and calretinin are markers for non-FSI, whereas GAD65 and GAD67 are expressed in all GABAergic interneurons. PV expression is significantly reduced in NR1neo-/- mice, whereas other proteins are unaffected. (c) No group differences are observed following in situ hybridization for PV mRNA, indicating that FSI are present, but disrupted, in NR1neo-/- mice. (d) Expression of postsynaptic GABAA- and GABAB-receptor subunits is measured by quantitative PCR (qPCR). The GABAA-receptor alpha-2 subunit is significantly upregulated in NR1neo-/- mice as seen in schizophrenia,55 whereas other subunits are unaffected. Graphs show mean +/- s.e.m., *P<0.05, **P<0.01, ***P<0.001. Reprinted by permission from Macmillan Publishers Ltd: Translational Psychiatry, GABAB-mediated rescue of altered excitatory–inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction, M J Gandal, J Sisti, K Klook, P I Ortinski, V Leitman, Y Liang, T Thieu, R Anderson, R C Pierce, G Jonak, R E Gur, G Carlson and S J Siegel, copyright – 2012. http://www.nature. com/tp/journal/v2/n7/full/tp201269a.html
Fig. (2)
Fig. (2)
Architecture of the trans-synaptic neurexin-neuroligin complex. Shown is: a) a synapse with presynaptic neurexins (NRXNs) and their postsynaptic binding partners neuroligins (NLGNs); receptors at the synapse. b) magnified view of the excitatory synapse with localization of NRXNs, NLGNs, PSD-95 which interacts with NLGNs through its third PDZ domain, the postsynaptic localization of AMPA receptors which are regulated by NLGNs and directly interact with them through an N-terminal interaction, and with PSD-95 (perhaps through stragazin?), and the location of SHANKs. Reprinted by permission from Macmillan Publishers Ltd: Nature, Neuroligins and neurexins link synaptic function to cognitive disease, Thomas C SÜdhof, 455, 903-911; copyright – 2008. http://www.nature.com/nature/ journal/v455/n7215/full/nature07456.html

Similar articles

See all similar articles

Cited by 14 articles

See all "Cited by" articles

References

    1. Diagnostic and Statistic Manual of Mental Disorders . 5th Edition. Vol. 991. Washington D C: American Psychiatric Publishing; 2013. American Psychiatric Association.
    1. Autism Developmental Disabilities Monitoring Network Surveillance Year 2008 Principal Investigators Center for Disease Control and Prevention Prevalence of autism spectrum disorders--Autism and Developmental Disabilities Monitoring Network 14 sites. United States 2008. 2012;61(3):1–19. - PubMed
    1. Thurm A, Swedo SE. The importance of autism research. Dialog. Clin. Neurosci. 2012;14(3):219–22. - PMC - PubMed
    1. Hollander E, Kolevzon A, Coyle JT, editors. Vol. 603. Washington D C: American Psychiatric Publishing.; 2011. Texbook of Autsim Spectrum Disorders.
    1. Bagni C, Tassone F, Neri G, Hagerman R. Fragile X syndrome: causes diagnosis mechanisms and therapeutics. J. Clin. Invest. 2012;22(12):4314–22. - PMC - PubMed
Feedback