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Gene X Environment Interactions in Cdh13-Deficient Mice: CDH13 As a Factor for Adaptation to the Environment

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Gene X Environment Interactions in Cdh13-Deficient Mice: CDH13 As a Factor for Adaptation to the Environment Gene x Environment Interactions in Cdh13-deficient Mice: CDH13 as a Factor for Adaptation to the Environment Gen x Umwelt-Interaktionen in Cdh13-defizienten Mäusen: CDH13 als ein Faktor für Umweltanpassung Doctoral thesis for a doctoral degree at the Graduate School of Life Sciences, Julius-Maximilians-Universität Würzburg, Section: Neuroscience Submitted by: Dominik Pascal Kiser from Detmold Würzburg, 2019 Submitted on: …………………………………… Office stamp Members of the Promotionskomitee: Chairperson: Prof. Dr. Paul Pauli Primary Supervisor: Prof. Dr. Klaus-Peter Lesch Supervisor (Second): Dr. Robert Blum Supervisor (Third): Prof. Dr. Flavio Roces Supervisor (Fourth): Dr. Daniel vanden Hove Date of Public Defence: …………………………………………….… Date of Receipt of Certificates: ………………………………………………. Index Index Index ....................................................................................................................................................................... 1 Abstract ................................................................................................................................................................. 3 Zusammenfassung ............................................................................................................................................ 5 1 Introduction ............................................................................................................................................... 7 1.1 ADHD and autism - disorders of genetic origin ................................................................ 7 1.2 Calcium-dependent cell adhesion molecule 13 (CDH13) ............................................. 9 1.2.1 Molecular structure and evolution of CDH13 ............................................................... 9 1.2.2 CDH13 during development .............................................................................................. 11 1.2.3 CDH13 in the adult brain ..................................................................................................... 12 1.2.4 CDH13 as a protective factor during cellular stress ................................................ 13 1.2.5 Summary of CDH13 and its brain-related to this thesis ........................................ 15 1.3 Effects of early-life stress on behaviour and development of NDDs ..................... 16 1.3.1 Models of early-life stress (ELS) in rodents ................................................................ 17 1.3.2 Consequences of early-life stress .................................................................................... 19 1.4 Hypothesis and objectives ....................................................................................................... 21 2 Methods ..................................................................................................................................................... 22 2.1 Animals ............................................................................................................................................. 22 2.2 Facility .............................................................................................................................................. 22 2.3 Maternal separation ................................................................................................................... 22 2.4 Behavioural tests ......................................................................................................................... 25 2.4.1 Elevated-plus-maze ............................................................................................................... 25 2.4.2 Light-dark box .......................................................................................................................... 25 2.4.3 Open-field test .......................................................................................................................... 26 2.4.4 Object-recognition test ......................................................................................................... 26 2.4.5 Barnes-maze ............................................................................................................................. 27 2.4.6 Step-down test ......................................................................................................................... 28 2.4.7 Context fear conditioning .................................................................................................... 29 2.5 Statistical analysis of the behavioural experiments ..................................................... 31 2.6 Brain extraction ............................................................................................................................ 31 2.7 Plasma corticosterone (CORT) measurement ................................................................. 31 2.8 Analysis of gene expression using quantitative real-time PCR (qRT-PCR) ........ 32 2.8.1 Dissection of brain regions ................................................................................................. 32 2.8.2 RNA isolation from brain tissue ....................................................................................... 33 2.8.3 Complementary DNA production .................................................................................... 34 2.8.4 Measurement of gene expression using qRT-PCR .................................................... 34 2.8.5 Statistical analysis of qRT-PCR data ............................................................................... 34 2.9 RNA sequencing ............................................................................................................................ 36 2.9.1 Preparation of RNA for Illumina sequencing .............................................................. 36 2.9.2 Statistical analysis of RNA sequencing data using the voom-lima pipeline .. 37 3 Results ........................................................................................................................................................ 38 3.1 Behavioural consequences of Cdh13 deficiency and maternal separation ......... 38 3.1.1 Elevated-plus-maze test ...................................................................................................... 38 3.1.2 Light-dark transition test .................................................................................................... 40 3.1.3 Open-field test .......................................................................................................................... 42 3.1.4 Object-recognition test ......................................................................................................... 44 1 Index 3.1.5 Barnes-maze test .................................................................................................................... 45 3.1.6 Step-down test ......................................................................................................................... 47 3.1.7 Context-fear conditioning test .......................................................................................... 48 3.2 CORT measurments .................................................................................................................... 49 3.3 Results of the quantitative real-time PCR ......................................................................... 50 3.3.1 Prefrontal cortex ..................................................................................................................... 50 3.3.2 Hippocampus ............................................................................................................................ 53 3.3.3 Dorsal/median raphe ............................................................................................................ 54 3.3.4 Amygdala .................................................................................................................................... 55 3.4 Effects of Cdh13 deficiency and MS on the expression of selected genes using Illumina RNA sequencing ........................................................................................................................ 58 3.4.1 Age as the strongest contributing factor ...................................................................... 58 3.4.2 Initial filtering and subsequent enrichment using GO/KEGG terms of changes due to Cdh13 deficiency in mice .................................................................................... 60 3.4.3 Manual screening of top 20 most significantly changed genes .......................... 64 4 Discussion ................................................................................................................................................. 72 4.1 Cdh13 deficiency modifies the response to MS and changes the balance of the serotonergic and GABAergic neurotransmitter systems .......................................................... 73 4.1.1 No adaptation to MS in Cdh13-deficient mice ............................................................ 73 4.1.2 Changes to the serotonergic system in the PFC and d/mRN ............................... 76 4.1.3 Cdh13 deficiency changes the GABAergic system of the PFC and AMY ........... 79 4.2 Learning and memory deficits due to MS and Cdh13 deficiency ............................. 81 4.3 Increased locomotion in female Cdh13-/- ........................................................................... 83 4.4 Increase in expression of
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