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

Nilsson, Simon R O; Celada, Pau; Fejgin, Kim; Thelin, Jonas LU ; Nielsen, Jacob; Santana, Noemí; Heath, Christopher J.; Larsen, Peter H.; Nielsen, Vibeke and Kent, Brianne A., et al. (2016) In Psychopharmacologia 233(11). p.2151-2163
Abstract

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... (More)

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 GABAAreceptor 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 GABAAreceptor 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.

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publication status
published
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keywords
15q13.3, Animal model, Chrna7, Cognition, Copy number variation, Neurophysiology, Prefrontal cortex
in
Psychopharmacologia
volume
233
issue
11
pages
13 pages
publisher
Springer
external identifiers
  • Scopus:84961216781
ISSN
0033-3158
DOI
10.1007/s00213-016-4265-2
language
English
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yes
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5d00dcf6-2fbb-461f-b01f-35405061abbf
date added to LUP
2016-07-11 11:20:34
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2016-10-30 04:48:46
@misc{5d00dcf6-2fbb-461f-b01f-35405061abbf,
  abstract     = {<p>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 GABA<sub>A</sub>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 GABA<sub>A</sub>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 α<sub>7</sub>nAChR 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.</p>},
  author       = {Nilsson, Simon R O and Celada, Pau and Fejgin, Kim and Thelin, Jonas and Nielsen, Jacob and Santana, Noemí and Heath, Christopher J. and Larsen, Peter H. and Nielsen, Vibeke and Kent, Brianne A. and Saksida, Lisa M. and Stensbøl, Tine B. and Robbins, Trevor W. and Bastlund, Jesper F. and Bussey, Timothy J. and Artigas, Francesc and Didriksen, Michael},
  issn         = {0033-3158},
  keyword      = {15q13.3,Animal model,Chrna7,Cognition,Copy number variation,Neurophysiology,Prefrontal cortex},
  language     = {eng},
  month        = {06},
  number       = {11},
  pages        = {2151--2163},
  publisher    = {ARRAY(0x939c7b0)},
  series       = {Psychopharmacologia},
  title        = {A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment},
  url          = {http://dx.doi.org/10.1007/s00213-016-4265-2},
  volume       = {233},
  year         = {2016},
}