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

Michael A van der Kooij; Martina Fantin; Igor Kraev; Irina Korshunova; Jocelyn Grosse; Olivia Zanoletti; Ramon Guirado; Clara Garcia-Mompó; Juan Nacher; Michael G Stewart; Vladimir Berezin; Carmen Sandi

doi:10.1038/npp.2013.315

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

Michael A van der Kooij, Martina Fantin, Igor Kraev, Irina Korshunova, Jocelyn Grosse, Olivia Zanoletti, Ramon Guirado, Clara Garcia-Mompó, Juan Nacher, Michael G Stewart, Vladimir Berezin, Carmen Sandi

45 Citations (Scopus)

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.

Original language	English
Journal	Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Volume	39
Issue number	5
Pages (from-to)	1148-1158
Number of pages	11
DOIs	https://doi.org/10.1038/npp.2013.315
Publication status	Published - Apr 2014

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van der Kooij, M. A., Fantin, M., Kraev, I., Korshunova, I., Grosse, J., Zanoletti, O., Guirado, R., Garcia-Mompó, C., Nacher, J., Stewart, M. G., Berezin, V., & Sandi, C. (2014). Impaired Hippocampal Neuroligin-2 Function by Chronic Stress or Synthetic Peptide Treatment is Linked to Social Deficits and Increased Aggression. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 39(5), 1148-1158. https://doi.org/10.1038/npp.2013.315

Impaired Hippocampal Neuroligin-2 Function by Chronic Stress or Synthetic Peptide Treatment is Linked to Social Deficits and Increased Aggression. / van der Kooij, Michael A; Fantin, Martina; Kraev, Igor et al.
In: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Vol. 39, No. 5, 04.2014, p. 1148-1158.

Research output: Contribution to journal › Journal article › Research › peer-review

van der Kooij, MA, Fantin, M, Kraev, I, Korshunova, I, Grosse, J, Zanoletti, O, Guirado, R, Garcia-Mompó, C, Nacher, J, Stewart, MG, Berezin, V & Sandi, C 2014, 'Impaired Hippocampal Neuroligin-2 Function by Chronic Stress or Synthetic Peptide Treatment is Linked to Social Deficits and Increased Aggression', Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, vol. 39, no. 5, pp. 1148-1158. https://doi.org/10.1038/npp.2013.315

van der Kooij MA, Fantin M, Kraev I, Korshunova I, Grosse J, Zanoletti O et al. Impaired Hippocampal Neuroligin-2 Function by Chronic Stress or Synthetic Peptide Treatment is Linked to Social Deficits and Increased Aggression. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2014 Apr;39(5):1148-1158. doi: 10.1038/npp.2013.315

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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.",

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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

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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 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.

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ER -

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

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