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.

Neuroligin 2 regulates spinal GABAergic plasticity in hyperalgesic priming, a model of the transition from acute to chronic pain

“…Based on these observations, we predict that interference with nlgn2 function should have differential effects in naive vs primed mice. We tested this using a newly discovered peptide (Neurolide 2 48 ; Fig. 6A) that selectively interferes with nlgn2 function.…”

Stress and the social brain: behavioural effects and neurobiological mechanisms

“…This fits with the concept of acute stress as a 'flight or fight' response 6 and implies that brief acute stressors mobilize resources to cope with the situation. Chronic stress (the stressor is recurrent or is sustained over several days) reduces social motivation and social interactions in a variety of sociability tests [13][14][15] , particularly in highly anxious animals 16 . For example, chronic social defeat induces social avoidance and social fear towards unknown conspecifics 17 , with the severity of these effects depending on the type and length of the defeat.…”

“…Social interactions with an animal's kin are also affected by chronic stress, as indicated by a disruption of paternal behavior and pairmate interactions in the monogamous, biparental California mouse (Peromyscus californicus) male subjected to chronic variable stress 19 . Aggressiveness is increased by chronic physical stressors -including chronic unpredictable mild stress 20 , restraint or immobilization [13][14][15]21 -in mice and rats, as well as by social stressors such as social isolation 18,22 in rodents and social and spatial restrictions in dogs 23 . Interestingly, chronic immobilization escalated both normative aggressive behavior (attacking small adversaries with a high chance of winning) and 'risky' aggression (attacking big adversaries, with a low chance of winning) in rats 21 .…”

“…Alterations in the neural E/I balance 203,204 are believed to underlie social deficits in psychiatric disorders, and chronic stress was shown to lead to an increase in the E/I balance 205,206,207 in the hippocampus of rodents. Chronic stress reduces NLGN-2, but not NLGN-1, expression throughout the hippocampus in parallel with decreased sociability and increased aggression in rats 13 [ figure, part c]. Hippocampal overexpression of NLGN-2 reduced aggressive behavior in rats 208 .…”

Regulation and postsynaptic binding of neurexins — drug targets for neurodevelopmental and neuropsychiatric disorders

“…Substantial evidence highlights that the NLGNs and NRXNs play important roles in the regulation of the neuronal excitation/inhibition (E/I) balance (Levinson and El-Husseini, 2005;Südhof, 2008). The NLGN:NRXN complex is also suggested to play critical roles in the maintenance and function of excitatory glutamatergic and inhibitory GABAergic synapses (Südhof, 2008;van der Kooij et al, 2014). In addition, mutations in Nlgns transgenic mice caused alterations in the E/I balance and abnormal social behaviors (Tabuchi et al, 2007;Hines et al, 2008;Jamain et al, 2008;Blundell et al, 2010;reviewed by van der Kooij et al, 2014).…”