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

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

doi:10.1007/s00213-016-4265-2

Abstract

RationaleA 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.ObjectivesThe objective of this study is to assess PFC-dependent functioning in the Df(h15q13)/+ mouse using electrophysiological, pharmacological, and behavioural assays.MethodExperiments 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.ResultsIn 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.ConclusionThe 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 materialThe online version of this article (doi:10.1007/s00213-016-4265-2) contains supplementary material, which is available to authorized users.

Highlights

The 15q13.3 microdeletion syndrome (15q13.3DS) is caused by a rare (∼1:30000 births) (LePichon et al 2010) copy number variant (CNV) with hemizygosity of at least seven genes on the long arm of chromosome 15
The Df(h15q13)/+ mouse has multiple dysfunctions converging on disrupted prefrontal cortical (PFC) processing as measured by several independent assays of inhibitory transmission and attentional function
The pathophysiology of schizophrenia is underpinned by imbalances within local prefrontal cortical (PFC) circuitry, typically observed as reductions in markers for cortical inhibitory signalling efficacy in histological (Lewis et al 2005) and neurophysiological assays (Daskalakis et al 2007; Javitt et al 2008)

Summary

Introduction

The 15q13.3 microdeletion syndrome (15q13.3DS) is caused by a rare (∼1:30000 births) (LePichon et al 2010) copy number variant (CNV) with hemizygosity of at least seven genes on the long arm of chromosome 15. The pathophysiology of schizophrenia is underpinned by imbalances within local prefrontal cortical (PFC) circuitry, typically observed as reductions in markers for cortical inhibitory signalling efficacy in histological (Lewis et al 2005) and neurophysiological assays (Daskalakis et al 2007; Javitt et al 2008). Deficits in executive functioning have been linked to dysregulated cortical recruitment and asynchronous activity partly produced by disrupted inhibitory activity during cognitive demand (Bickel and Javitt 2009; Nakazawa et al 2012). The critical 15q13.3 segment encompasses the CHRNA7 gene, which is involved in cortical inhibitory transmission (Adams et al 2012; Lin et al 2014), regulates schizophrenia-relevant neurophysiological markers (Hajos et al 2005), and is associated with attentional dysfunction (Adler et al 1998; Young et al 2004). The 15q13.3DS has been associated with attentional impairments that can be independent of general intellectual functioning (Miller et al 2009)

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