TY - JOUR

T1 - Impaired Hippocampal Neuroligin-2 Function by Chronic Stress or Synthetic Peptide Treatment is Linked to Social Deficits and Increased Aggression

AU - van der Kooij, Michael A

AU - Fantin, Martina

AU - Kraev, Igor

AU - Korshunova, Irina

AU - Grosse, Jocelyn

AU - Zanoletti, Olivia

AU - Guirado, Ramon

AU - Garcia-Mompó, Clara

AU - Nacher, Juan

AU - Stewart, Michael G

AU - Berezin, Vladimir

AU - Sandi, Carmen

PY - 2014/11/11

Y1 - 2014/11/11

N2 - 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 NRXN1, 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.Neuropsychopharmacology accepted article preview online, 11 November 2013. doi:10.1038/npp.2013.315.

AB - 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 NRXN1, 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.Neuropsychopharmacology accepted article preview online, 11 November 2013. doi:10.1038/npp.2013.315.

U2 - 10.1038/npp.2013.315

DO - 10.1038/npp.2013.315

M3 - Journal article

C2 - 24213355

VL - 39

SP - 1148

EP - 1158

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

SN - 0893-133X

IS - 5

ER -