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...
Autores principales: | , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1782432366857289728 |
---|---|
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. |
format | Online Article Text |
id | pubmed-4869740 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT nilssonsimonro amousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT celadapau amousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT fejginkim amousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT thelinjonas amousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT nielsenjacob amousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT santananoemi amousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT heathchristopherj amousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT larsenpeterh amousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT nielsenvibeke amousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT kentbriannea amousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT saksidalisam amousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT stensbøltineb amousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT robbinstrevorw amousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT bastlundjesperf amousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT busseytimothyj amousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT artigasfrancesc amousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT didriksenmichael amousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT nilssonsimonro mousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT celadapau mousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT fejginkim mousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT thelinjonas mousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT nielsenjacob mousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT santananoemi mousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT heathchristopherj mousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT larsenpeterh mousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT nielsenvibeke mousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT kentbriannea mousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT saksidalisam mousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT stensbøltineb mousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT robbinstrevorw mousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT bastlundjesperf mousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT busseytimothyj mousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT artigasfrancesc mousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment AT didriksenmichael mousemodelofthe15q133microdeletionsyndromeshowsprefrontalneurophysiologicaldysfunctionsandattentionalimpairment |