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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 and Didriksen, Michael
(2016).
DOI: https://doi.org/10.1007/s00213-016-4265-2
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 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.
Results
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.
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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About
- Item ORO ID
- 45754
- Item Type
- Journal Item
- ISSN
- 1432-2072
- Keywords
- copy number variation; 15q13.3; animal model; Chrna7; prefrontal cortex; neurophysiology; cognition
- Academic Unit or School
-
Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM) - Research Group
- Neuroscience Research Group
- Copyright Holders
- © 2016 The Authors
- Depositing User
- Christopher Heath