LSID: http://syli.cz/urn:lsid:public.sylics.com:experiment:DEA2-G4A8-2987
| Treatment | Amount | Administration route | Administration time |
Treatment info:
Order of behavioural testing
PhenoTyper Spontaneous Behaviour
PhenoTyper Appetitive Conditioning
PhenoTyper Avoidance Learning
Body Weight
Grip Strength
Novel Home Cage Induced Hypophagia
Elevated Plus Maze
Open Field
Novel Object Recognition
Dark/Light Box
Rotorod
T-Maze
Barnes Maze
Fear Conditioning
Acoustic Startle Response and Prepulse Inhibition
Forced Swim Test
Published in Neuroscience 2015:
http://www.sciencedirect.com/science/article/pii/S0306452215004893
Functional characterization of the PCLO p.Ser4814Ala variant associated with major depressive disorder reveals cellular but not behavioral differences
Giniatullina A1, Maroteaux G1, Geerts CJ1, Koopmans B2, Loos M2, Klaassen R3, Chen N3, van der Schors RC3, van Nierop P3, Li KW3, de Jong J1, Altrock WD4, Cornelisse LN5, Toonen RF1, van der Sluis S5, Sullivan PF6, Stiedl O7, Posthuma D8, Smit AB3, Groffen AJ9, Verhage M10.
1Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands.
2Sylics (Synaptologics BV), Amsterdam, The Netherlands.
3Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands.
4Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, Magdeburg, Germany.
5Department of Clinical Genetics, Section Complex Trait Genetics, VU University Medical Center, Amsterdam, The Netherlands.
6Department of Genetics, University of North Carolina, Chapel Hill, NC, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
7Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands; Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands.
8Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
9Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
10Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands; Department of Clinical Genetics, Section Complex Trait Genetics, VU University Medical Center, Amsterdam, The Netherlands.
Abstract
Genome-wide association studies have suggested a role for a genetic variation in the presynaptic gene PCLO in major depressive disorder (MDD). As with many complex traits, the PCLO variant has a small contribution to the overall heritability and the association does not always replicate. One variant (rs2522833, p.Ser4814Ala) is of particular interest given that it is a common, nonsynonymous exon variant near a calcium-sensing part of PCLO. It has been suggested that the molecular effects of such variations penetrate to a variable extent in the population due to phenotypic and genotypic heterogeneity at the population level. More robust effects may be exposed by studying such variations in isolation, in a more homogeneous context. We tested this idea by modeling PCLO variation in a mouse knock-in model expressing the Pclo(SA)(/)(SA) variant. In the highly homogeneous background of inbred mice, two functional effects of the SA-variation were observed at the cellular level: increased synaptic Piccolo levels, and 30% increased excitatory synaptic transmission in cultured neurons. Other aspects of Piccolo function were unaltered: calcium-dependent phospholipid binding, synapse formation in vitro, and synaptic accumulation of synaptic vesicles. Moreover, anxiety, cognition and depressive-like behavior were normal in Pclo(SA)(/)(SA) mice. We conclude that the PCLO p.Ser4814Ala missense variant produces mild cellular phenotypes, which do not translate into behavioral phenotypes. We propose a model explaining how (subtle) cellular phenotypes do not penetrate to the mouse behavioral level but, due to genetic and phenotypic heterogeneity and non-linearity, can produce association signals in human population studies.
Mouse info:
| Mouse ID | Strain | Coat color | Genotype | Ear tag | Internal ID | Sex | Date of Birth | Sub experiment 1 | Sub experiment 2 | Sub experiment 3 |
| PH05004 | Pclo(SA) | black | hom | RL | 8077 | male | 13-03-2012 | |||
| PH05005 | Pclo(SA) | black | hom | RR | 8078 | male | 13-03-2012 | |||
| PH05006 | Pclo(SA) | black | hom | R | 8081 | male | 13-03-2012 | |||
| PH05007 | Pclo(SA) | black | WT | RL | 8083 | male | 13-03-2012 | |||
| PH05008 | Pclo(SA) | black | WT | RR | 8084 | male | 13-03-2012 | |||
| PH05009 | Pclo(SA) | black | WT | - | 8086 | male | 13-03-2012 | |||
| PH05010 | Pclo(SA) | black | hom | RL | 8089 | male | 13-03-2012 | |||
| PH05011 | Pclo(SA) | black | hom | RR | 8090 | male | 13-03-2012 | |||
| PH05012 | Pclo(SA) | black | WT | LL | 8091 | male | 13-03-2012 | |||
| PH05013 | Pclo(SA) | black | WT | L | 8094 | male | 13-03-2012 | |||
| PH05014 | Pclo(SA) | black | WT | R | 8099 | male | 13-03-2012 | |||
| PH05015 | Pclo(SA) | black | hom | L | 8100 | male | 13-03-2012 | |||
| PH05016 | Pclo(SA) | black | hom | L | 8112 | male | 13-03-2012 | |||
| PH05017 | Pclo(SA) | black | WT | - | 8116 | male | 13-03-2012 | |||
| PH05018 | Pclo(SA) | black | WT | R | 8123 | male | 15-03-2012 | |||
| PH05019 | Pclo(SA) | black | WT | L | 8124 | male | 15-03-2012 | |||
| PH05020 | Pclo(SA) | black | hom | RL | 8125 | male | 15-03-2012 | |||
| PH05021 | Pclo(SA) | black | WT | LL | 8127 | male | 15-03-2012 | |||
| PH05022 | Pclo(SA) | black | hom | R | 8129 | male | 15-03-2012 | |||
| PH05023 | Pclo(SA) | black | WT | RR | 8132 | male | 15-03-2012 | |||
| PH05024 | Pclo(SA) | black | hom | R | 8135 | male | 15-03-2012 | |||
| PH05025 | Pclo(SA) | black | hom | RL | 8137 | male | 15-03-2012 | |||
| PH05026 | Pclo(SA) | black | hom | LL | 8139 | male | 15-03-2012 | |||
| PH05027 | Pclo(SA) | black | WT | R | 8141 | male | 16-03-2012 | |||
| PH05028 | Pclo(SA) | black | hom | L | 8535 | male | 17-03-2012 | |||
| PH05029 | Pclo(SA) | black | hom | RL | 8536 | male | 17-03-2012 | |||
| PH05030 | Pclo(SA) | black | WT | RR | 8537 | male | 17-03-2012 | |||
| PH05031 | Pclo(SA) | black | WT | - | 8539 | male | 20-03-2012 | |||
| PH05032 | Pclo(SA) | black | hom | R | 8540 | male | 20-03-2012 | |||
| PH05033 | Pclo(SA) | black | WT | RR | 8543 | male | 20-03-2012 | |||
| PH05034 | Pclo(SA) | black | WT | R | 8546 | male | 20-03-2012 | |||
| PH05035 | Pclo(SA) | black | hom | L | 8547 | male | 20-03-2012 |