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

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.

Sex Hormones Regulate SHANK Expression

“…SHANK genes reside on autosomes, and SHANK variants are randomly distributed across male and female subjects. So far, only copy number variant (CNV) deletions encompassing the SHANK1 gene segregated in male carriers with high-functioning autism and showed a clearly reduced penetrance in female individuals (Sato et al, 2012 ) and some SHANK variants have been found in male autistic patients that were inherited from healthy mothers (for a recent review see (Eltokhi et al, 2018 )).…”

“…SHANK proteins (SHANK1, SHANK2 and SHANK3) are scaffolding proteins at the postsynaptic site of excitatory synapses in the central nervous system (Kreienkamp, 2008 ), crucial for the formation, organization and signaling of excitatory synapses. SHANK gene variants have been associated with ASD, intellectual disability and schizophrenia (Leblond et al, 2014 ; Eltokhi et al, 2018 ).…”

Shank2 Mutant Mice Display Hyperactivity Insensitive to Methylphenidate and Reduced Flexibility in Social Motivation, but Normal Social Recognition

“…In the present study, we focused our experiments on mice lacking the Shank2 protein. To date, three different genetic constructions of the model exist (reviewed in Eltokhi et al, 2018 ): deletion of exon 16 [knock out ( Schmeisser et al, 2012 ; Ey et al, 2013 ; Lim et al, 2016 ), conditional knock out in Purkinje cells ( Peter et al, 2016 )], deletion of exons 15 and 16 [knock out ( Won et al, 2012 ; Lee et al, 2015 ; Lim et al, 2016 ), conditional knock out in Purkinje cells ( Ha et al, 2016 ), conditional knock out in excitatory neurons ( Kim et al, 2018 ), conditional knock out in inhibitory neurons ( Kim et al, 2018 ), conditional knock out in parvalbumin-positive neurons ( Lee et al, 2018 )], deletion of exon 24 [knock out ( Pappas et al, 2017 ), conditional knock out in Purkinje cells ( Pappas et al, 2017 ), conditional knock out in excitatory neurons of neocortex and hippocampus ( Pappas et al, 2017 )]. All these models display hyperactivity, except the mice mutated conditionally only in Purkinje cells ( Ha et al, 2016 ; Peter et al, 2016 ; Pappas et al, 2017 ).…”

Behavioral tests assessing neuropsychiatric phenotypes in adolescent mice reveal strain- and sex-specific effects

“…Moreover, it contributed to our understanding of genetic and molecular mechanisms underlying complex behaviors, such as circadian rhythm, anxiety, and cognitive functions 16 . This progress is based on establishing a variety of assays for mouse behavioral phenotyping which has been developed over the years to maximize the scope and reproducibility of findings, minimize artifacts and false-positive results and provide robust and valid translational tools for testing hypotheses and developing novel treatments 17,18 .…”

“…Behavioral tests in mice are mostly burdened by inherent complexity and require consideration of several aspects such as sources of variability and experimental interference that could preclude spontaneous behavior 19 . The choice of the behavioral test is another important issue, and several tests exist for different behavioral categories covering a wide range of neuropsychiatric symptoms 18 . Furthermore, recapitulating the behavioral features of a human disease is a prerequisite for the translation of preclinical results into clinical applications 20 .…”