Abstract
The correlation between dysfunction in the glutamatergic system and neuropsychiatric disorders, including schizophrenia and autism spectrum disorder, is undisputed. Both disorders are associated with molecular and ultrastructural alterations that affect synaptic plasticity and thus the molecular and physiological basis of learning and memory. Altered synaptic plasticity, accompanied by changes in protein synthesis and trafficking of postsynaptic proteins, as well as structural modifications of excitatory synapses, are critically involved in the postnatal development of the mammalian nervous system. In this review, we summarize glutamatergic alterations and ultrastructural changes in synapses in schizophrenia and autism spectrum disorder of genetic or drug-related origin, and briefly comment on the possible reversibility of these neuropsychiatric disorders in the light of findings in regular synaptic physiology.
Highlights
The correlation between dysfunction in the glutamatergic system and neuropsychiatric disorders, including schizophrenia and autism spectrum disorder, is undisputed
Multiple subunits encoded by 18 different genes can contribute to the formation of iGluRs. Most of these subunits derive from different mRNA splice or premRNA edited variants of genes coding for iGluR subunits, which increase the complexity of the ionotropic glutamatergic neurotransmission system. Based on their main agonist, iGluRs are divided into α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs), N-methyl-D-aspartate receptors (NMDARs), and kainate receptors (KARs)
In the hippocampal CA1 region of a VRK3-deficient mouse model of Autism Spectrum Disorder (ASD), prominent reductions in postsynaptic density (PSD) length and thickness were revealed [143]. Adding another layer of complexity, a mouse model of Phelan–McDermid syndrome causing autistic phenotypes with a deficiency of mitogen-activated protein kinase 8 interacting protein 2 (MAPK8IP2/IB2), which plays an important role in regulating the ratio of AMPARs to NMDARs at glutamate synapses, revealed no synaptic ultrastructure alterations of cerebellar glutamatergic synapses and featured normal synaptic clefts and postsynaptic densities and abundant presynaptic vesicles [252]
Summary
Excitatory neurotransmission in the brain is primarily glutamatergic; glutamatergic neurons in the non-stimulated cerebral cortex consume up to 80% of the total brain metabolic activity [1,2,3]. Most of these subunits derive from different mRNA splice or premRNA edited variants of genes coding for iGluR subunits, which increase the complexity of the ionotropic glutamatergic neurotransmission system Based on their main agonist, iGluRs are divided into α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs), N-methyl-D-aspartate receptors (NMDARs), and kainate receptors (KARs). NMDAR currents, and groups II and III inhibit presynaptic glutamate release [7] This molecular complexity of the glutamate sensing system suggests that the glutamate receptors play a major role in the experience-dependent modulation of the CNS. The structural organization and numbers of synapses are modified postnatally, demonstrating that the maturation of synaptic transmission and plasticity is accompanied by a structural reorganization of synapses (see below) In this process, glutamatergic postsynaptic scaffolding proteins such as the SH3 and multiple ankyrin domain proteins (SHANKs) appear to play a central role. NMDAR and AMPAR Ca2+ signaling lead to a dysfunction of neuron-to-neuron communication, neuronal network dynamics, and responses to environmental stimuli, as detailed below
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