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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.

Distinct Phenotypes of Shank2 Mouse Models Reflect Neuropsychiatric Spectrum Disorders of Human Patients With SHANK2 Variants