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

Simon R O Nilsson; Pau Celada; Kim Fejgin; Jonas Thelin; Jacob Nielsen; Noemí Santana; Christopher J. Heath; Peter H. Larsen; Vibeke Nielsen; Brianne A. Kent; Lisa M. Saksida; Tine B. Stensbøl; Trevor W. Robbins; Jesper F. Bastlund; Timothy J. Bussey; Francesc Artigas; Michael Didriksen

doi:10.1007/s00213-016-4265-2

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

Simon R O Nilsson, Pau Celada, Kim Fejgin, Jonas Thelin, Jacob Nielsen, Noemí Santana, Christopher J. Heath, Peter H. Larsen, Vibeke Nielsen, Brianne A. Kent, Lisa M. Saksida, Tine B. Stensbøl, Trevor W. Robbins, Jesper F. Bastlund, Timothy J. Bussey, Francesc Artigas, Michael Didriksen

Neuronano Research Center (NRC)

Research output: Contribution to journal › Article › peer-review

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 pyramidal firing in response to intra-PFC GABA_Areceptor 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_Areceptor 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.

Original language	English
Pages (from-to)	2151-2163
Number of pages	13
Journal	Psychopharmacologia
Volume	233
Issue number	11
DOIs	https://doi.org/10.1007/s00213-016-4265-2
Publication status	Published - 2016 Jun 1

Subject classification (UKÄ)

Pharmaceutical Sciences

Free keywords

15q13.3
Animal model
Chrna7
Cognition
Copy number variation
Neurophysiology
Prefrontal cortex

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10.1007/s00213-016-4265-2

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Nilsson, S. R. O., Celada, P., Fejgin, K., Thelin, J., Nielsen, J., Santana, N., Heath, C. J., Larsen, P. H., Nielsen, V., Kent, B. A., Saksida, L. M., Stensbøl, T. B., Robbins, T. W., Bastlund, J. F., Bussey, T. J., Artigas, F., & Didriksen, M. (2016). A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment. Psychopharmacologia, 233(11), 2151-2163. https://doi.org/10.1007/s00213-016-4265-2

@article{5d00dcf62fbb461fb01f35405061abbf,

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

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 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.",

keywords = "15q13.3, Animal model, Chrna7, Cognition, Copy number variation, Neurophysiology, Prefrontal cortex",

author = "Nilsson, {Simon R O} and Pau Celada and Kim Fejgin and Jonas Thelin and Jacob Nielsen and Noem{\'i} Santana and Heath, {Christopher J.} and Larsen, {Peter H.} and Vibeke Nielsen and Kent, {Brianne A.} and Saksida, {Lisa M.} and Stensb{\o}l, {Tine B.} and Robbins, {Trevor W.} and Bastlund, {Jesper F.} and Bussey, {Timothy J.} and Francesc Artigas and Michael Didriksen",

year = "2016",

month = jun,

day = "1",

doi = "10.1007/s00213-016-4265-2",

language = "English",

volume = "233",

pages = "2151--2163",

journal = "Psychopharmacologia",

issn = "0033-3158",

publisher = "Springer Science and Business Media B.V.",

number = "11",

}

Nilsson, SRO, Celada, P, Fejgin, K, Thelin, J, Nielsen, J, Santana, N, Heath, CJ, Larsen, PH, Nielsen, V, Kent, BA, Saksida, LM, Stensbøl, TB, Robbins, TW, Bastlund, JF, Bussey, TJ, Artigas, F & Didriksen, M 2016, 'A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment', Psychopharmacologia, vol. 233, no. 11, pp. 2151-2163. https://doi.org/10.1007/s00213-016-4265-2

TY - JOUR

T1 - A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment

AU - Nilsson, Simon R O

AU - Celada, Pau

AU - Fejgin, Kim

AU - Thelin, Jonas

AU - Nielsen, Jacob

AU - Santana, Noemí

AU - Heath, Christopher J.

AU - Larsen, Peter H.

AU - Nielsen, Vibeke

AU - Kent, Brianne A.

AU - Saksida, Lisa M.

AU - Stensbøl, Tine B.

AU - Robbins, Trevor W.

AU - Bastlund, Jesper F.

AU - Bussey, Timothy J.

AU - Artigas, Francesc

AU - Didriksen, Michael

PY - 2016/6/1

Y1 - 2016/6/1

N2 - 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.

AB - 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.

KW - 15q13.3

KW - Animal model

KW - Chrna7

KW - Cognition

KW - Copy number variation

KW - Neurophysiology

KW - Prefrontal cortex

UR - http://www.scopus.com/inward/record.url?scp=84961216781&partnerID=8YFLogxK

U2 - 10.1007/s00213-016-4265-2

DO - 10.1007/s00213-016-4265-2

M3 - Article

C2 - 26983414

AN - SCOPUS:84961216781

SN - 0033-3158

VL - 233

SP - 2151

EP - 2163

JO - Psychopharmacologia

JF - Psychopharmacologia

IS - 11

ER -

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

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