Abstract
The SHANK scaffolding proteins are important organizers for signaling proteins in the postsynapse of excitatory neurons. The functional significance of SHANK proteins becomes apparent by the wide spectrum of neurodevelopmental and neuropsychiatric disorders associated with SHANK variants in human patients. A similar diversity of neuropsychiatric-like phenotypes is described for numerous Shank2 and Shank3 knockout (KO) mouse lines. In this review, we will focus on and discuss the experimental results obtained from different, but genetically related and therefore comparable, Shank2 mouse models. First, we will describe the distinct SHANK2 variant-mediated neurodevelopmental and neuropsychiatric disorders in human patients. Then we will discuss the current knowledge of the expressed SHANK2 isoforms in the mouse, and we will describe the genetic strategies used for generating three conventional and seven conditional Shank2 mouse lines. The distinct impairments i.e., autistic-like and mania-like behavior and the alterations on the molecular, electrophysiological and behavioral levels will be compared between the different Shank2 mouse models. We will present our view as to why in these mouse models a spectrum of phenotypes can arise from similar Shank2 gene manipulations and how Shank2 mutant mice can be used and should be analyzed on the behavioral level in future research.
Highlights
guanylate kinase-associated protein (GKAP) itself can bind to the postsynaptic density molecule 95 (PSD95; Naisbitt et al, 1997) that is in contact with the glutamate gated ion channels, N-methyl-D-aspartate receptors (NMDAR) (Kornau et al, 1995) and AMPAR (Kim et al, 2001; Uemura et al, 2004; for review see Boeckers et al, 2002)
The comparison between Shank2 KO mouse lines strongly suggests that truncated SHANK2 isoforms or their mRNAs disrupt the homeostasis of SHANK proteins and their function as major scaffolding organizers in the postsynaptic matrix
The Shank2 mutant mice showed that autism spectrum disorders (ASD)-related symptoms can be diminished by pharmacological treatment of the mutant mice, which can guide future therapeutic strategies for ASD patients
Summary
Gene variants of the multi-domain postsynaptic scaffolding proteins included in the SHANK family ( known as ProSAP) are significantly associated with autism spectrum disorders (ASD). In all 10 different Shank KO mouse lines, the gene KO strategies were very similar leading to protein products truncated within the PDZ domain or the PRR, both present in all SHANK2 isoforms of the WT mice (Figure 1). Mutations in Different Protein Interaction Domains As outlined above, the comprehensive analysis of patients harboring SHANK2 alterations with neurodevelopmental and neuropsychiatric disorders revealed a wide range of phenotypic expression, with various symptoms of ASD, ID, and SCZ. Some synonymous variants appear in patients with ASD, ID and SCZ, but not in healthy controls (Berkel et al, 2010; Rauch et al, 2012; TABLE 2 | Five single point mutations in the coding region (c.) of the SHANK2 gene leading to five amino acid residue exchanges (p.) that are associated with different neuropsychiatric disorders. References c.1604A >G c.1730C >T c.1759C >T c.1829C >A c.5191G >T p.K535R p.A577V p.P587S p.S610Y p.A1731S
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