Abstract
The 22q11.2 deletion syndrome (22q11.2DS) confers high risk of neurodevelopmental disorders such as schizophrenia and attention-deficit hyperactivity disorder. These disorders are associated with attentional impairment, the remediation of which is important for successful therapeutic intervention. We assessed a 22q11.2DS mouse model (Df(h22q11)/+) on a touchscreen rodent continuous performance test (rCPT) of attention and executive function that is analogous to human CPT procedures. Relative to wild-type littermates, Df(h22q11)/+ male mice showed impaired attentional performance as shown by decreased correct response ratio (hit rate) and a reduced ability to discriminate target stimuli from non-target stimuli (discrimination sensitivity, or d’). The Df(h22q11)/+ model exhibited decreased prefrontal cortical-hippocampal oscillatory synchrony within multiple frequency ranges during quiet wakefulness, which may represent a biomarker of cognitive dysfunction. The stimulant amphetamine (0–1.0 mg/kg, i.p.) dose-dependently improved d’ in Df(h22q11)/+ mice whereas the highest dose of modafinil (40 mg/kg, i.p.) exacerbated their d’ impairment. This is the first report to directly implicate attentional impairment in a 22q11.2DS mouse model, mirroring a key endophenotype of the human disorder. The capacity of the rCPT to detect performance impairments in the 22q11.2DS mouse model, and improvement following psychostimulant-treatment, highlights the utility and translational potential of the Df(h22q11)/+ model and this automated behavioral procedure.
Highlights
A copy number variant (CNV) composed of a hemizygous microdeletion at chromosomal locus 22q11.2 confers large genetic risk for schizophrenia[1], attentiondeficit hyperactivity disorder (ADHD)[2] and autism[3]
To further characterize the Df(h22q11)/+ mouse model, we investigated prefrontal cortical (PFC)-hippocampal coherence which has been proposed as an endophenotype of several neuropsychiatric disorders associated with 22q11.2DS, including schizophrenia[32]
A second older cohort of Df(h22q11)/+mice, with extensive previous cognitive testing experience, showed decreased target hit rates when challenged with shorter stimulus durations (Supplementary Fig. S1a–b; genotype × SD: F5,130 = 4.795, p < 0.0001) and increased response criterion c when challenged with longer inter-stimulus interval (ISI) times (Supplementary Fig. S2c–d; genotype × ISI: F2,50 = 3.221, p = 0.048)
Summary
A copy number variant (CNV) composed of a hemizygous microdeletion at chromosomal locus 22q11.2 confers large genetic risk for schizophrenia[1], attentiondeficit hyperactivity disorder (ADHD)[2] and autism[3]. The 22q11.2 microdeletion syndrome (22q11.2DS) and its related neuropsychiatric disorders are associated with executive and attentional impairments[4]. These deficits are of central interest for translational[5] and genetic studies[6] aimed at discovering more effective therapeutics. Visual target or non-target stimuli are briefly presented at a fixed screen location across a series of continuous, sequential trials. Non-affected individuals with high genetic load of schizophrenia-related genetic variants[8], and 22q11.2 deletion carriers[7,9,10,11,12], show impaired
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