Modeling a model: Mouse genetics, 22q11.2 Deletion Syndrome, and disorders of cortical circuit development

Abstract

Understanding the developmental etiology of autistic spectrum disorders, attention deficit/hyperactivity disorder and schizophrenia remains a major challenge for establishing new diagnostic and therapeutic approaches to these common, difficult-to-treat diseases that compromise neural circuits in the cerebral cortex. One aspect of this challenge is the breadth and overlap of ASD, ADHD, and SCZ deficits; another is the complexity of mutations associated with each, and a third is the difficulty of analyzing disrupted development in at-risk or affected human fetuses. The identification of distinct genetic syndromes that include behavioral deficits similar to those in ASD, ADHC and SCZ provides a critical starting point for meeting this challenge. We summarize clinical and behavioral impairments in children and adults with one such genetic syndrome, the 22q11.2 Deletion Syndrome, routinely called 22q11DS, caused by micro-deletions of between 1.5 and 3.0 MB on human chromosome 22. Among many syndromic features, including cardiovascular and craniofacial anomalies, 22q11DS patients have a high incidence of brain structural, functional, and behavioral deficits that reflect cerebral cortical dysfunction and fall within the spectrum that defines ASD, ADHD, and SCZ. We show that developmental pathogenesis underlying this apparent genetic “model” syndrome in patients can be defined and analyzed mechanistically using genomically accurate mouse models of the deletion that causes 22q11DS. We conclude that “modeling a model”, in this case 22q11DS as a model for idiopathic ASD, ADHD and SCZ, as well as other behavioral disorders like anxiety frequently seen in 22q11DS patients, in genetically engineered mice provides a foundation for understanding the causes and improving diagnosis and therapy for these disorders of cortical circuit development.

22q11.2 deletion syndrome

“…As a regulator of the Ran complex, this protein has multiple functions — including cilia formation and modulation of mitosis — that may contribute to the CNS and other phenotypes of 22q11.2DS 117 . Evidence for a role in neurogenesis places RANBP1 as a candidate for the cortical circuits implicated in disorders associated with 22q11.2DS, such as attention-deficit disorders, autism and schizophrenia 79,117 .…”

“…Loss of Tbx1 may be partially rescued by hemizygosity of Trp53 , implicating histone methylation as a mechanism and suggesting potential pharmacological strategies that could compensate for developmental defects associated with 22q11.2 deletions 98 . Defective cortical circuitry and some abnormalities of signalling, for instance, in Sonic Hedgehog and CXC chemokine receptor 4 ( Cxcr4 )– CXC chemokine ligand 12 ( Cxcl12 ; also known as Sdf1 ) signalling, which are important in interneuron migration, have been detected in the brains of mouse deletion models that may involve a DGCR8 -mediated miRNA mechanism and have relevance for schizophrenia in the general population 79,122 .…”

A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium

“…The expectations are that the biological pathways identified may be similar to those for individuals with schizophrenia without the 22q11.2 deletion, and that the elevated risk in 22q11DS will provide an enhanced effect size to identify the salient genetic factors and systems involved. 14–16 …”

“…85 Other resources will also be used to prioritize the schizophrenia-related variants identified in 22q11DS, including in silico analyses of potential function (including regulatory function) using animal model data and human tissue expression data. 16 To adjust for multiple testing while avoiding overcorrection in analyses that involve inherently correlated data (for example, testing two pathways that may have genetic overlap), various methods may be applied, for example, using permutation or other standard methods (for example, Benjamini–Hochberg false discovery rate). 15,74 To appreciate the overall genomic architecture of schizophrenia in 22q11DS will require eventual integration of all genomic variant findings with the phenotypic data, and other downstream analyses to investigate potential disease mechanism and function 16 using actual animal models, tissue expression profiles and spatiotemporal expression profiles during brain development (Figure 2).…”

Altered Brain Structure-Function Relationships Underlie Executive Dysfunction in 22q11.2 Deletion Syndrome

“…The precise mechanism is not fully understood, but it is plausible that abnormalities in cortical thickness may result from reduced dosage of genes involved in cortical development. These differences in cortical thickness between 22q11DS patients and controls are likely to play a role in the executive dysfunction characteristic of the disorder [84]. The relationship between cortical thickness and cognition in healthy individuals is complex, and a relatively thinner cortex may have different consequences, depending on the developmental context [45,72,78,85].…”