AHCODA-DB

Experiment name: Functional characterization of the PCLO p.Ser4814Ala variant associated with major depressive disorder. (Giniatullina 2015)
LSID: http://syli.cz/urn:lsid:public.sylics.com:experiment:DEA2-G4A8-2987

TreatmentAmountAdministration routeAdministration 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