Genetic variability in scaffolding proteins and risk for schizophrenia and autism-spectrum disorders: a systematic review

Abstract

Scaffolding proteins represent an evolutionary solution to controlling the specificity of information transfer in intracellular networks. They are highly concentrated in complexes located in specific subcellular locations. One of these complexes is the postsynaptic density of the excitatory synapses. There, scaffolding proteins regulate various processes related to synaptic plasticity, such as glutamate receptor trafficking and signalling, and dendritic structure and function. Most scaffolding proteins can be grouped into 4 main families: discs large (DLG), discs-large-associated protein (DLGAP), Shank and Homer. Owing to the importance of scaffolding proteins in postsynaptic density architecture, it is not surprising that variants in the genes that code for these proteins have been associated with neuropsychiatric diagnoses, including schizophrenia and autism-spectrum disorders. Such evidence, together with the clinical, neurobiological and genetic overlap described between schizophrenia and autism-spectrum disorders, suggest that alteration of scaffolding protein dynamics could be part of the pathophysiology of both. However, despite the potential importance of scaffolding proteins in these psychiatric conditions, no systematic review has integrated the genetic and molecular data from studies conducted in the last decade. This review has the following goals: to systematically analyze the literature in which common and/or rare genetic variants (single nucleotide polymorphisms, single nucleotide variants and copy number variants) in the scaffolding family genes are associated with the risk for either schizophrenia or autism-spectrum disorders; to explore the implications of the reported genetic variants for gene expression and/or protein function; and to discuss the relationship of these genetic variants to the shared genetic, clinical and cognitive traits of schizophrenia and autism-spectrum disorders.

Fig. 1

Image of the postsynaptic density (PSD) and scheme of the scaffolding proteins at the PSD that have been analyzed in the present review. (A) An electronic microscope image of a synapse; vesicles can be observed in the presynaptic neuron (asterisk). The electron-dense structure observed in the postsynaptic element is the PSD (arrowhead). Scale bar, 250 nm. Image retrieved under the Creative Commons Attribution License from Heupel et al. Neural Devel 2008, https://doi.org/10.1186/1749-8104-3-25. (B) A scheme of the PSD (grey shading). Multimerization of Shank1 to 3 proteins generate a network that links numerous proteins to the postsynaptic receptors. Homer proteins, including Homer1b/c, Homer2 and Homer3, also act as adaptors and interact with several PSD proteins, such as type I-mGluRs. The DLGAP1 to 4 proteins interact with DLG proteins, including the DLG1/SAP-97, DLG2/PSD-93, DLG3/SAP-102 and DLG4/PSD-95, to coregulate different ion channels, such as the NMDAR and AMPAR. AMPAR = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; DLG = discs large; DLGAP = discs-large-associated protein; mGluR = metabotropic glutamate receptor; NMDAR = N-methyl-d-aspartate receptor; SAP = synapse-associated protein.

Fig. 2

Flow diagram of the literature search. PSD = postsynaptic density.