Journal Article

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

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

2016

Overview

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.

• Publisher: Springer Berlin Heidelberg,Springer,Springer Nature B.V
• Subject: Animals / Attention / Attention Deficit Disorder with Hyperactivity - genetics / Attention Deficit Disorder with Hyperactivity - physiopathology / Attention Deficit Disorder with Hyperactivity - psychology / Basic Medicine / Behavior, Animal - drug effects / Biomedical and Life Sciences / Biomedicine / Chromosome Deletion / Chromosome Disorders - genetics / Chromosomes, Human, Pair 15 - genetics / Disease Models, Animal / Evoked Potentials, Auditory - drug effects / Extinction, Psychological - drug effects / Farmaceutiska vetenskaper / GABA Antagonists - pharmacology / Gene Deletion / Genetic aspects / Health aspects / Humans / Intellectual Disability - genetics / Interneurons - drug effects / Male / Medical and Health Sciences / Medical research / Medicin och hälsovetenskap / Medicine, Experimental / Medicinska och farmaceutiska grundvetenskaper / Mice / Mice, Inbred C57BL / Neurology / Neurophysiology / Neurosciences / Original Investigation / Pharmaceutical Sciences / Pharmacology/Toxicology / Physiological psychology / Prefrontal cortex / Prefrontal Cortex - physiopathology / Psychiatry / Psychopharmacology / Pyramidal Cells - drug effects / Pyridazines - pharmacology / Reaction Time - drug effects / Receptors, GABA-A - drug effects / Reversal Learning - drug effects / Schizophrenia / Schizophrenia - genetics / Schizophrenia - physiopathology / Schizophrenic Psychology / Seizures - genetics