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

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.

SUBMITTER: Nilsson SRO

PROVIDER: S-EPMC6235862 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Nilsson Simon R O SRO Heath Christopher J CJ Takillah Samir S Didienne Steve S Fejgin Kim K Nielsen Vibeke V Nielsen Jacob J Saksida Lisa M LM Mariani Jean J Faure Philippe P Didriksen Michael M Robbins Trevor W TW Bussey Timothy J TJ Mar Adam C AC

Translational psychiatry 20181114 1

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 ...[more]

PMID: 30429456

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Project description:Although progress has been made, the cognitive, biological and, particularly, the genetic underpinnings of math learning difficulties (MD) remain largely unknown. This difficulty stems from the heterogeneity of MD and from the large contribution of environmental factors to its etiology. Understanding endophenotypes, e.g., the role of the Approximate Number System (ANS), may help understanding the nature of MD. MD associated with ANS impairments has been described in some genetic conditions, e.g., 22q11.2 deletion syndrome (22q11.2DS or Velocardiofacial syndrome, VCFS). Recently, a girl with MD was identified in a school population screening. She has a new syndrome resulting from a microdeletion in 22q11.2 (LCR22-4 to LCR22-5), a region adjacent to but not overlapping with region 22q11.2 (LCR22-2 to LCR22-4), typically deleted in VCFS. Here, we describe her cognitive-neuropsychological and numerical-cognitive profiles. The girl was assessed twice, at 8 and 11 years. Her numerical-cognitive performance at both times was compared to demographically similar girls with normal intelligence in a single-case, quasi-experimental study. Neuropsychological assessment was normal, except for relatively minor impairments in executive functions. She presented severe and persistent difficulties in the simplest single-digit calculations. Difficulties in commutative operations improved from the first to the second assessment. Difficulties in subtraction persisted and were severe. No difficulties were observed in Arabic number writing. Difficulties in single-digit calculation co-occurred with basic numerical processing impairments in symbolic and non-symbolic (single-digit comparison, dot sets size comparison and estimation) tasks. Her difficulties suggest ANS impairment. No difficulties were detected in visuospatial/visuoconstructional and in phonological processing tasks. The main contributions of the present study are: (a) this is the first characterization of the neuropsychological phenotype in 22q11.2DS (LCR22-4 to LCR22.5) with normal intelligence; (b) mild forms of specific genetic conditions contribute to persistent MD in otherwise typical persons; (c) heterogeneity of neurogenetic underpinnings of MD is suggested by poor performance in non-symbolic numerical processing, dissociated from visuospatial/visuoconstructional and phonological impairments; (d) similar to what happens in 22q11.2DS (LCR22-2 to LCR22-4), ANS impairments may also characterize 22q11.2DS (LCR22-4 to LCR22-5).

Project description:RationaleA microdeletion at locus 15q13.3 is associated with high incidence rates of psychopathology, including schizophrenia. A mouse model of the 15q13.3 microdeletion syndrome has been generated (Df[h15q13]/+) with translational utility for modelling schizophrenia-like pathology. Among other deficits, schizophrenia is characterised by dysfunctions in prefrontal cortical (PFC) inhibitory circuitry and attention.ObjectivesThe objective of this study is to assess PFC-dependent functioning in the Df(h15q13)/+ mouse using electrophysiological, pharmacological, and behavioural assays.MethodExperiments 1-2 investigated baseline firing and auditory-evoked responses of PFC interneurons and pyramidal neurons. Experiment 3 measured pyramidal firing in response to intra-PFC GABAA receptor antagonism. Experiments 4-6 assessed PFC-dependent attentional functioning through the touchscreen 5-choice serial reaction time task (5-CSRTT). Experiments 7-12 assessed reversal learning, paired-associate learning, extinction learning, progressive ratio, trial-unique non-match to sample, and object recognition.ResultsIn experiments 1-3, the Df(h15q13)/+ mouse showed reduced baseline firing rate of fast-spiking interneurons and in the ability of the GABAA receptor antagonist gabazine to increase the firing rate of pyramidal neurons. In assays of auditory-evoked responses, PFC interneurons in the Df(h15q13)/+ mouse had reduced detection amplitudes and increased detection latencies, while pyramidal neurons showed increased detection latencies. In experiments 4-6, the Df(h15q13)/+ mouse showed a stimulus duration-dependent decrease in percent accuracy in the 5-CSRTT. The impairment was insensitive to treatment with the partial α7nAChR agonist EVP-6124. The Df(h15q13)/+ mouse showed no cognitive impairments in experiments 7-12.ConclusionThe Df(h15q13)/+ mouse has multiple dysfunctions converging on disrupted PFC processing as measured by several independent assays of inhibitory transmission and attentional function.

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

Publications

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

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