Assessing the Cognitive Translational Potential of a Mouse Model of the 22q11.2 Microdeletion Syndrome

Abstract

A chromosomal microdeletion at the 22q11.2 locus is associated with extensive cognitive impairments, schizophrenia and other psychopathology in humans. Previous reports indicate that mouse models of the 22q11.2 microdeletion syndrome (22q11.2DS) may model the genetic basis of cognitive deficits relevant for neuropsychiatric disorders such as schizophrenia. To assess the models usefulness for drug discovery, a novel mouse (Df(h22q11)/+) was assessed in an extensive battery of cognitive assays by partners within the NEWMEDS collaboration (Innovative Medicines Initiative Grant Agreement No. 115008). This battery included classic and touchscreen-based paradigms with recognized sensitivity and multiple attempts at reproducing previously published findings in 22q11.2DS mouse models. This work represents one of the most comprehensive reports of cognitive functioning in a transgenic animal model. In accordance with previous reports, there were non-significant trends or marginal impairment in some tasks. However, the Df(h22q11)/+ mouse did not show comprehensive deficits; no robust impairment was observed following more than 17 experiments and 14 behavioral paradigms. Thus -within the current protocols -the 22q11.2DS mouse model fails to mimic the cognitive alterations observed in human 22q11.2 deletion carriers. We suggest that the 22q11.2DS model may induce liability for cognitive dysfunction with additional "hits" being required for phenotypic expression.

Continuous performance test impairment in a 22q11.2 microdeletion mouse model: improvement by amphetamine

“…This deficit has been commonly ascribed to an impairment in working memory and has been linked to prefrontal cortical (PFC)-hippocampal asynchrony within theta and gamma bands 20 , 24 . However, the T-maze impairment in the 22q11.2DS mouse model appears transient and delay-independent—inconsistent with a primary deficit in working memory 23 . PFC-hippocampal synchrony is also associated with executive function and/or attentional processes in other behavioral paradigms 26 – 28 .…”

“…Figure 1 depicts the experimental timeline of this study. The behavioral experiments were performed at the University of Cambridge and used two cohorts of male mice housed as previously described 23 . Sample sizes were selected based on previous rCPT experiments 30 and similar touchscreen paradigms 40 .…”

“…Several mouse models of 22q11.2DS have been generated 15 – 19 . Studies investigating the performance of these models across multiple cognitive domains, including associative and spatial learning, flexibility, and memory, have yielded equivocal results 19 – 23 . One of the consistent behavioral impairments in these models is an acquisition deficit on a T-maze delayed non-match to position task 19 , 23 – 25 .…”

“…Studies investigating the performance of these models across multiple cognitive domains, including associative and spatial learning, flexibility, and memory, have yielded equivocal results 19 – 23 . One of the consistent behavioral impairments in these models is an acquisition deficit on a T-maze delayed non-match to position task 19 , 23 – 25 . This deficit has been commonly ascribed to an impairment in working memory and has been linked to prefrontal cortical (PFC)-hippocampal asynchrony within theta and gamma bands 20 , 24 .…”

“…There is a paucity of studies evaluating attentional function in 22q11.2DS mouse models 29 . One recent study assessed divided visuospatial attention using the 5-choice serial reaction time task (5-CSRTT) and reported either no effect, or paradoxically improved performance after extended training, in the Df(h22q11)/+ model 23 . However, to date, there have been no assessments of focused visual attention in 22q11.2DS mouse models.…”