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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.

SUBMITTER: van der Kooij MA

PROVIDER: S-EPMC3957108 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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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 MA Fantin Martina M Kraev Igor I Korshunova Irina I Grosse Jocelyn J Zanoletti Olivia O Guirado Ramon R Garcia-Mompó Clara C Nacher Juan J Stewart Michael G MG Berezin Vladimir V Sandi Carmen C

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20131111 5

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 dif ...[more]

PMID: 24213355

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Project description:Autism spectrum disorders (ASDs) comprise a heterogeneous group of neuro-developmental abnormalities with a strong genetic component, characterized by deficits in verbal and non-verbal communication, impaired social interactions, and stereotyped behaviors. In a small percentage of cases, ASDs are associated with alterations of genes involved in synaptic function. Among these, relatively frequent are mutations/deletions of genes encoding for neuroligins (NLGs). NLGs are postsynaptic adhesion molecules that, interacting with their presynaptic partners neurexins, ensure the cross talk between pre- and postsynaptic specializations and synaptic stabilization, a condition needed for maintaining a proper excitatory/inhibitory balance within local neuronal circuits. We have focused on mice lacking NLG3 (NLG3 knock-out mice), animal models of a non-syndromic form of autism, which exhibit deficits in social behavior reminiscent of those found in ASDs. Among different brain areas involved in social cognition, the CA2 region of the hippocampus has recently emerged as a central structure for social memory processing. Here, in vivo recordings from anesthetized animals and ex vivo recordings from hippocampal slices have been used to assess the dynamics of neuronal signaling in the CA2 hippocampal area. In vivo experiments from NLG3-deficient mice revealed a selective impairment of spike-related slow wave activity in the CA2 area and a significant reduction in oscillatory activity in the theta and gamma frequencies range in both CA2 and CA3 regions of the hippocampus. These network effects were associated with an increased neuronal excitability in the CA2 hippocampal area. Ex vivo recordings from CA2 principal cells in slices obtained from NLG3 knock-out animals unveiled a strong excitatory/inhibitory imbalance in this region accompanied by a strong reduction of perisomatic inhibition mediated by CCK-containing GABAergic interneurons. These data clearly suggest that the selective alterations in network dynamics and GABAergic signaling observed in the CA2 hippocampal region of NLG3 knock-out mice may account for deficits in social memory reminiscent of those observed in autistic patients.

Project description:Monoamine oxidase (MAO)-A is a key enzyme for the degradation of brain serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE). In humans and mice, total MAO-A deficiency results in high 5-HT and NE levels, as well as elevated reactive aggression. Here we report the generation of MAO-A(Neo) mice, a novel line of hypomorphic MAO-A mutants featuring the insertion of a floxed neomycin-resistance cassette in intron-12 of the Maoa gene. This construct resulted in a chimeric, non-functional variant of the Maoa-Neo transcript, with a truncated C-terminus, likely due to aberrant splicing; these deficits notwithstanding, small amounts of functional Maoa transcript were found in the brain of MAO-A(Neo) mice. In the prefrontal cortex and amygdala, MAO-A(Neo) mice showed low, yet detectable, MAO-A catalytic activity, as well as 5-HT levels equivalent to WT littermates; conversely, the hippocampus and midbrain of MAO-A(Neo) mice featured a neurochemical profile akin to MAO-A-knockout (KO) mice, with undetectable MAO-A activity and high 5-HT concentrations. MAO-A(Neo) mice showed significant increases in dendritic length in the pyramidal neurons of orbitofrontal cortex, but not basolateral amygdala, in comparison with WT littermates; by contrast, the orbitofrontal cortex of MAO-A KO mice showed significant reductions in basilar dendritic length, as well as a profound increase in apical dendritic length. MAO-A(Neo) mice showed a unique set of behavioral abnormalities, encompassing reduced open-field locomotion, perseverative responses, such as marble burying and water mist-induced grooming, and a lack of anxiety-like behaviors in the elevated plus-maze and light-dark box paradigms. Notably, whereas MAO-A(Neo) and KO mice showed significant reductions in social interaction, only the latter genotype showed increases in resident-intruder aggression. Taken together, our findings indicate that MAO A hypomorphism results in behavioral and morphological alterations distinct from those featured by MAO-A KO mice.

Dataset Information

Impaired hippocampal neuroligin-2 function by chronic stress or synthetic peptide treatment is linked to social deficits and increased aggression.

Publications

Impaired hippocampal neuroligin-2 function by chronic stress or synthetic peptide treatment is linked to social deficits and increased aggression.

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