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

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 de...

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Autores principales: Nilsson, Simon R. O., Celada, Pau, Fejgin, Kim, Thelin, Jonas, Nielsen, Jacob, Santana, Noemí, Heath, Christopher J., Larsen, Peter H., Nielsen, Vibeke, Kent, Brianne A., Saksida, Lisa M., Stensbøl, Tine B., Robbins, Trevor W., Bastlund, Jesper F., Bussey, Timothy J., Artigas, Francesc, Didriksen, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869740/
https://www.ncbi.nlm.nih.gov/pubmed/26983414
http://dx.doi.org/10.1007/s00213-016-4265-2
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author Nilsson, Simon R. O.
Celada, Pau
Fejgin, Kim
Thelin, Jonas
Nielsen, Jacob
Santana, Noemí
Heath, Christopher J.
Larsen, Peter H.
Nielsen, Vibeke
Kent, Brianne A.
Saksida, Lisa M.
Stensbøl, Tine B.
Robbins, Trevor W.
Bastlund, Jesper F.
Bussey, Timothy J.
Artigas, Francesc
Didriksen, Michael
author_facet Nilsson, Simon R. O.
Celada, Pau
Fejgin, Kim
Thelin, Jonas
Nielsen, Jacob
Santana, Noemí
Heath, Christopher J.
Larsen, Peter H.
Nielsen, Vibeke
Kent, Brianne A.
Saksida, Lisa M.
Stensbøl, Tine B.
Robbins, Trevor W.
Bastlund, Jesper F.
Bussey, Timothy J.
Artigas, Francesc
Didriksen, Michael
author_sort Nilsson, Simon R. O.
collection PubMed
description 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(A) 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(A) 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(7)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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00213-016-4265-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-48697402016-06-21 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 Nielsen, Jacob Santana, Noemí Heath, Christopher J. Larsen, Peter H. Nielsen, Vibeke Kent, Brianne A. Saksida, Lisa M. Stensbøl, Tine B. Robbins, Trevor W. Bastlund, Jesper F. Bussey, Timothy J. Artigas, Francesc Didriksen, Michael Psychopharmacology (Berl) Original Investigation 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(A) 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(A) 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(7)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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00213-016-4265-2) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2016-03-17 2016 /pmc/articles/PMC4869740/ /pubmed/26983414 http://dx.doi.org/10.1007/s00213-016-4265-2 Text en © The Author(s) 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Investigation
Nilsson, Simon R. O.
Celada, Pau
Fejgin, Kim
Thelin, Jonas
Nielsen, Jacob
Santana, Noemí
Heath, Christopher J.
Larsen, Peter H.
Nielsen, Vibeke
Kent, Brianne A.
Saksida, Lisa M.
Stensbøl, Tine B.
Robbins, Trevor W.
Bastlund, Jesper F.
Bussey, Timothy J.
Artigas, Francesc
Didriksen, Michael
A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment
title A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment
title_full A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment
title_fullStr A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment
title_full_unstemmed A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment
title_short A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment
title_sort mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869740/
https://www.ncbi.nlm.nih.gov/pubmed/26983414
http://dx.doi.org/10.1007/s00213-016-4265-2
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