Role of adhesion proteins Neuroligin 2 and IgSF9b in the amygdala anxiety circuitry

by Olga Babaev
Doctoral thesis
Date of Examination:2017-06-01
Date of issue:2018-04-23
Advisor:Prof. Dr. Nils Brose
Referee:Ph.d. Camin Dean
Referee:Prof. Dr. Dr. Hannelore Ehrenreich
Persistent Address: http://dx.doi.org/10.53846/goediss-6841

 

 

Files in this item

Name:Babaev Olga Thesis.pdf
Size:5.08Mb
Format:PDF

The following license files are associated with this item:

Abstract

English

Anxiety disorder is a debilitating condition that affects up to 10% of the adult population in the world. Mapping of brain activity in patients and in mouse models has shown that anxiety- related behavior is associated with abnormally high firing of basal amygdala and its downstream target nucleus, the centromedial amygdala. A plausible mechanism for this increased excitatory drive is dysfunction of amygdala inhibitory synapses, but the proteins that contribute to such dysfunction and that may serve as novel targets for pharmaceutical intervention are largely unknown. Here, I investigate the function of two synaptic adhesion proteins implicated in neuropsychiatric disorders, Neuroligin 2 (Nlgn2) and IgSF9b, at inhibitory synapses in the anxiety- processing circuitry in amygdala. Using a combination of behavioral assessment, quantitative morphological analysis, cFOS induction assay, anatomical tracing and in vivo and in vitro electrophysiology, I show that deletion of Nlgn2 causes a prominent anxiety phenotype and results in upregulation of activity of excitatory projection neurons in basal amygdala, which in turn robustly enhance the firing of centromedial amygdala under anxiogenic conditions. To identify additional inhibitory synaptic proteins involved in anxiety regulation, I investigated the function of IgSF9b, a novel cell adhesion molecule that interacts with Nlgn2 in vitro and hence potentially modulates the anxiety phenotype of Nlgn2 KO mice. I show that in sharp contrast to Nlgn2 KO mice, deletion of IgSF9b decreases anxiety behavior and enhances the activation of inhibitory interneurons in basal amygdala under anxiogenic conditions. Moreover, deletion of each protein affects distinct subsets of inhibitory synapses in basal and centromedial amygdala. Strikingly, those differential mechanisms interact in mice lacking both proteins to completely rescue anxiety phenotype by normalizing the anxiety- associated firing of centromedial amygdala. Specifically, deletion of IgSF9b rescues the enhancement of high gamma (70-120 Hz) band activity of centromedial amygdala in Nlgn2 KO mice during exposure to anxiogenic conditions. My findings indicate that Nlgn2 and IgSF9b play a crucial role in anxiety processing, thus providing important insights into the molecular mechanisms of anxiety and into potential drug targets for anxiety treatment.
Keywords: Amygdala; Anxiety; Neuroligin 2; IgSF9b; Basal amygdala; Centromedial amygdala; Parvalbumin; Neural oscillations
 
Statistik