title: Impaired hippocampal neuroligin-2 function by chronic stress or synthetic peptide treatment is linked to social deficits and increased aggression.
abstract: Neuroligins (NLGNs) are cell adhesion molecules that are important for proper synaptic formation and functioning, and are critical regulators of the balance between neural excitation/inhibition (E/I). Mutations in NLGNs have been linked to psychiatric disorders in humans involving social dysfunction and are related to similar abnormalities in animal models. Chronic stress increases the likelihood for affective disorders and has been shown to induce changes in neural structure and function in different brain regions, with the hippocampus being highly vulnerable to stress. Previous studies have shown evidence of chronic stress-induced changes in the neural E/I balance in the hippocampus. Therefore, we hypothesized that chronic restraint stress would lead to reduced hippocampal NLGN-2 levels, in association with alterations in social behavior. We found that rats submitted to chronic restraint stress in adulthood display reduced sociability and increased aggression. This occurs along with a reduction of NLGN-2, but not NLGN-1 expression (as shown with western blot, immunohistochemistry, and electron microscopy analyses), throughout the hippocampus and detectable in different layers of the CA1, CA3, and DG subfields. Furthermore, using synthetic peptides that comprise sequences in either NLGN-1 (neurolide-1) or NLGN-2 (neurolide-2) involved in the interaction with their presynaptic partner neurexin (NRXN)-1, intra-hippocampal administration of neurolide-2 led also to reduced sociability and increased aggression. These results highlight hippocampal NLGN-2 as a key molecular substrate regulating social behaviors and underscore NLGNs as promising targets for the development of novel drugs for the treatment of dysfunctional social behaviors.
authors.affiliation: Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne EPFL, Lausanne, Switzerland.
authors.forename: Michael A
authors.initials: MA
authors.lastname: van der Kooij
authors.affiliation: Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne EPFL, Lausanne, Switzerland.
authors.forename: Martina
authors.initials: M
authors.lastname: Fantin
authors.affiliation: Department of Life Sciences, The Open University, Milton Keynes, UK.
authors.forename: Igor
authors.initials: I
authors.lastname: Kraev
authors.affiliation: The Laboratory of Neural Plasticity, Department of Neurosciences and Pharmacology, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Irina
authors.initials: I
authors.lastname: Korshunova
authors.affiliation: Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne EPFL, Lausanne, Switzerland.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Grosse
authors.affiliation: Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne EPFL, Lausanne, Switzerland.
authors.forename: Olivia
authors.initials: O
authors.lastname: Zanoletti
authors.affiliation: Cell Biology Department, Neurobiology Unit and Program in Basic and Applied Neurosciences, Universitat de València, Valencia, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Guirado
authors.affiliation: Cell Biology Department, Neurobiology Unit and Program in Basic and Applied Neurosciences, Universitat de València, Valencia, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Garcia-Mompó
authors.affiliation: Cell Biology Department, Neurobiology Unit and Program in Basic and Applied Neurosciences, Universitat de València, Valencia, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Nacher
authors.affiliation: Department of Life Sciences, The Open University, Milton Keynes, UK.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Stewart
authors.affiliation: The Laboratory of Neural Plasticity, Department of Neurosciences and Pharmacology, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Berezin
authors.affiliation: Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne EPFL, Lausanne, Switzerland.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sandi
mesh_terms: D000374:Aggression / Q000502:physiology*; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002908:Chronic Disease; D003345:Corticosterone / Q000097:blood; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000502:physiology; D009929:Organ Size; D010455:Peptides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000378:metabolism; D012149:Restraint, Physical; D012919:Social Behavior; D013315:Stress, Psychological / Q000473:pathology / Q000503:physiopathology*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D009419:Nerve Tissue Proteins; C547193:Nrxn1 protein, rat; D010455:Peptides; D011956:Receptors, Cell Surface; C093438:neuroligin 1; C098003:neuroligin 2; D003345:Corticosterone