title: Hypersocial behavior and biological redundancy in mice with reduced expression of PSD95 or PSD93.
abstract: The postsynaptic density proteins 95 (PSD95) and 93 (PSD93) belong to a family of scaffolding proteins, the membrane-associated guanylate kinases (MAGUKs), which are highly enriched in synapses and responsible for organizing the numerous protein complexes required for synaptic development and plasticity. Genetic studies have associated MAGUKs with diseases like autism and schizophrenia, but knockout mice show severe, complex defects with difficult-to-interpret behavioral abnormalities due to major motor dysfunction which is atypical for psychiatric phenotypes. Therefore, rather than studying loss-of-function mutants, we comprehensively investigated the behavioral consequences of reduced PSD95 expression, using heterozygous PSD95 knockout mice (PSD95+/-). Specifically, we asked whether heterozygous PSD95 deficient mice would exhibit alterations in the processing of social stimuli and social behavior. Additionally, we investigated whether PSD95 and PSD93 would reveal any indication of functional or biological redundancy. Therefore, homozygous and heterozygous PSD93 deficient mice were examined in a similar behavioral battery as PSD95 mutants. We found robust hypersocial behavior in the dyadic interaction test in both PSD95+/-males and females. Additionally, male PSD95+/-mice exhibited higher levels of aggression and territoriality, while female PSD95+/-mice showed increased vocalization upon exposure to an anesthetized female mouse. Both male and female PSD95+/-mice revealed mild hypoactivity in the open field but no obvious motor deficit. Regarding PSD93 mutants, homozygous (but not heterozygous) knockout mice displayed prominent hypersocial behavior comparable to that observed in PSD95+/-mice, despite a more severe motor phenotype, which precluded several behavioral tests or their interpretation. Considering that PSD95 and PSD93 reduction provoke strikingly similar behavioral consequences, we explored a potential substitution effect and found increased PSD93 protein expression in hippocampal synaptic enrichment preparations of PSD95+/-mice. These data suggest that both PSD95 and PSD93 are involved in processing of social stimuli and control of social behavior. This important role may be partly assured by functional/behavioral and biological/biochemical redundancy.
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Germany; DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Winkler
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Germany; Laboratory of Neurosciences, Federal University of Sao Carlos, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Daher
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Germany.
authors.forename: Liane
authors.initials: L
authors.lastname: Wüstefeld
authors.affiliation: Cognitive Ethology Laboratory, German Primate Center, Göttingen, Germany.
authors.forename: Kurt
authors.initials: K
authors.lastname: Hammerschmidt
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Germany; Neurobiology Department, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Giulia
authors.initials: G
authors.lastname: Poggi
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Seelbach
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Germany.
authors.forename: Dilja
authors.initials: D
authors.lastname: Krueger-Burg
authors.affiliation: Neurobiology Department, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Behnam
authors.initials: B
authors.lastname: Vafadari
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Ronnenberg
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center, Göttingen, Germany.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Neurobiology Department, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Leszek
authors.initials: L
authors.lastname: Kaczmarek
authors.affiliation: DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany; Department of Psychiatry and Psychotherapy, University Medical Center, Göttingen, Germany.
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Schlüter
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Germany; DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany. Electronic address: ehrenreich@em.mpg.de.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Ehrenreich
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Germany; DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany. Electronic address: dere@em.mpg.de.
authors.forename: Ekrem
authors.initials: E
authors.lastname: Dere
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D000076122:Disks Large Homolog 4 Protein / Q000172:deficiency* / Q000235:genetics; D005260:Female; D051528:Guanylate Kinases / Q000172:deficiency* / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D012919:Social Behavior
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; C501445:Dlg2 protein, mouse; D051528:Guanylate Kinases
keywords: Aggression; Biological redundancy; Dyadic social interaction; Hypoactivity; Social blindness; Substitution effect; Ultrasonic vocalization