Enhanced cognition and dysregulated hippocampal synaptic physiology in mice with a heterozygous deletion of PSD‐95 |
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| Authors: | Alexa E. Horner Catherine L. McLaughlin Nurudeen O. Afinowi Timothy J. Bussey Lisa M. Saksida Noboru H. Komiyama Seth G. N. Grant Maksym V. Kopanitsa |
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| Affiliation: | 1. Synome Ltd, Cambridge, UK;2. Genes to Cognition Programme, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK;3. Department of Psychology, University of Cambridge, Cambridge, UK;4. The MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK;5. Molecular Medicine Research Group, Robarts Research Institute, London, ON, Canada;6. Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada |
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| Abstract: | PSD‐95 is one of the most abundant proteins of the postsynaptic density of excitatory synapses. It functions as the backbone of protein supercomplexes that mediate signalling between membrane glutamate receptors and intracellular pathways. Homozygous deletion of the Dlg4 gene encoding PSD‐95 was previously found to cause a profound impairment in operant and Pavlovian conditioning in Dlg4?/? mice studied in touch screen chambers that precluded evaluation of PSD‐95's role in shaping more subtle forms of learning and memory. In this study, using a battery of touch screen tests, we investigated cognitive behaviour of mice with a heterozygous Dlg4 mutation. We found that in contrast to learning deficits of Dlg4?/? mice, Dlg4+/? animals demonstrated enhanced performance in the Visual Discrimination, Visual Discrimination Reversal and Paired‐Associates Learning touch screen tasks. The divergent directions of learning phenotypes observed in Dlg4?/? and Dlg4+/? mice also contrasted with qualitatively similar changes in the amplitude and plasticity of field excitatory postsynaptic potentials recorded in the CA1 area of hippocampal slices from both mutants. Our results have important repercussions for the studies of genetic models of human diseases, because they demonstrate that reliance on phenotypes observed solely in homozygous mice may obscure qualitatively different changes in heterozygous animals and potentially weaken the validity of translational comparisons with symptoms seen in heterozygous human carriers. |
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| Keywords: | hippocampal slice paired‐associates learning reversal learning touch screen visual discrimination |
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