title: A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment.
abstract: 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.
  
  
  
  The objective of this study is to assess PFC-dependent functioning in the Df(h15q13)/+ mouse using electrophysiological, pharmacological, and behavioural assays.
  
  
  
  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.
  
  
  
  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.
  
  
  
  The Df(h15q13)/+ mouse has multiple dysfunctions converging on disrupted PFC processing as measured by several independent assays of inhibitory transmission and attentional function.
authors.affiliation: Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, UK. sn440@cam.ac.uk.|MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK. sn440@cam.ac.uk.|Department of Psychology, State University of New York at Binghamton, Binghamton, NY, 13902-6000, USA. sn440@cam.ac.uk.
authors.forename: Simon R O
authors.initials: SRO
authors.lastname: Nilsson
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona, CSIC-IDIBAPS, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain.
authors.forename: Pau
authors.initials: P
authors.lastname: Celada
authors.affiliation: H. Lundbeck A/S, Synaptic Transmission, Neuroscience Research DK, Ottiliavej 9, Valby, 2500, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Fejgin
authors.affiliation: H. Lundbeck A/S, Synaptic Transmission, Neuroscience Research DK, Ottiliavej 9, Valby, 2500, Denmark.|Neuronano Research Center, Lund University, 223 81, Lund, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Thelin
authors.affiliation: H. Lundbeck A/S, Synaptic Transmission, Neuroscience Research DK, Ottiliavej 9, Valby, 2500, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Nielsen
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona, CSIC-IDIBAPS, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain.
authors.forename: Noemí
authors.initials: N
authors.lastname: Santana
authors.affiliation: Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, UK.|MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK.|Department of Life, Health and Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Heath
authors.affiliation: H. Lundbeck A/S, Synaptic Transmission, Neuroscience Research DK, Ottiliavej 9, Valby, 2500, Denmark.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Larsen
authors.affiliation: H. Lundbeck A/S, Synaptic Transmission, Neuroscience Research DK, Ottiliavej 9, Valby, 2500, Denmark.
authors.forename: Vibeke
authors.initials: V
authors.lastname: Nielsen
authors.affiliation: Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, UK.|MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK.
authors.forename: Brianne A
authors.initials: BA
authors.lastname: Kent
authors.affiliation: Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, UK.|MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Saksida
authors.affiliation: H. Lundbeck A/S, Synaptic Transmission, Neuroscience Research DK, Ottiliavej 9, Valby, 2500, Denmark.
authors.forename: Tine B
authors.initials: TB
authors.lastname: Stensbøl
authors.affiliation: Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, UK.|MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK.
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
authors.affiliation: H. Lundbeck A/S, Synaptic Transmission, Neuroscience Research DK, Ottiliavej 9, Valby, 2500, Denmark.
authors.forename: Jesper F
authors.initials: JF
authors.lastname: Bastlund
authors.affiliation: Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, UK.|MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Bussey
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona, CSIC-IDIBAPS, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Artigas
authors.affiliation: H. Lundbeck A/S, Synaptic Transmission, Neuroscience Research DK, Ottiliavej 9, Valby, 2500, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Didriksen
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000503:physiopathology* / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D004195:Disease Models, Animal; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D005108:Extinction, Psychological / Q000187:drug effects; D018756:GABA Antagonists / Q000494:pharmacology; D017353:Gene Deletion; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D007395:Interneurons / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000503:physiopathology*; D017966:Pyramidal Cells / Q000187:drug effects; D011724:Pyridazines / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects; D012193:Reversal Learning / Q000187:drug effects; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*; D012565:Schizophrenic Psychology; D012640:Seizures / Q000235:genetics
chemical_list: D018756:GABA Antagonists; D011724:Pyridazines; D011963:Receptors, GABA-A; C049853:gabazine
keywords: 15q13.3; Animal model; Chrna7; Cognition; Copy number variation; Neurophysiology; Prefrontal cortex