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A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment.

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Nilsson, Simon RO 
Celada, Pau 
Fejgin, Kim 
Thelin, Jonas 
Nielsen, Jacob 


RATIONALE: A 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. OBJECTIVES: The objective of this study is to assess PFC-dependent functioning in the Df(h15q13)/+ mouse using electrophysiological, pharmacological, and behavioural assays. METHOD: Experiments 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. RESULTS: In 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. CONCLUSION: The Df(h15q13)/+ mouse has multiple dysfunctions converging on disrupted PFC processing as measured by several independent assays of inhibitory transmission and attentional function.



15q13.3, Animal model, Chrna7, Cognition, Copy number variation, Neurophysiology, Prefrontal cortex, Animals, Attention Deficit Disorder with Hyperactivity, Behavior, Animal, Chromosome Deletion, Chromosome Disorders, Chromosomes, Human, Pair 15, Disease Models, Animal, Evoked Potentials, Auditory, Extinction, Psychological, GABA Antagonists, Gene Deletion, Humans, Intellectual Disability, Interneurons, Male, Mice, Mice, Inbred C57BL, Prefrontal Cortex, Pyramidal Cells, Pyridazines, Reaction Time, Receptors, GABA-A, Reversal Learning, Schizophrenia, Schizophrenic Psychology, Seizures

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Psychopharmacology (Berl)

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Springer Science and Business Media LLC
Medical Research Council (G1000183)
Wellcome Trust (093875/Z/10/Z)
European Commission (115008)
Medical Research Council (G0001354)
The research leading to these results has received support from the Innovative Medicine Initiative Joint Undertaking under grant agreement n° 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013). The Behavioural and Clinical Neuroscience Institute is co-funded by the Medical Research Council and the Wellcome Trust. This study was also supported by the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). The authors would like to thank Mercedes Nuñez, Noemí Jurado, Edita Bulovaitė, Sueda Tunçak, Lewis Buss, and Diab Ali for skillful technical assistance.