Project Description:
Anxiety disorders are among the most common mental disorders in the US. Current methods to treat anxiety, sedatives, provide temporary relief but do not address the root cause. We hypothesize that experience-dependent plasticity via nicotinic acetylcholine receptors (nAChRs) plays a role in the development of learned anxiety triggers by altering excitatory/inhibitory balance in the amygdala. We find that experience development plasticity underlies the heightened anxiety in a mouse model of anxiety, lynx2KO mice. LYNX2 is a good candidate as a novel target to alleviate anxiety as it is highly expressed in anxiety regions, such as the amygdala, and lynx2KO mice exhibit heightened anxiety in multiple measures (light-dark box, thigmotaxis, elevated plus maze, etc.).
Lynx family members (lynx1, lynx2, etc.) form stable complexes with nicotinic receptors of the cholinergic system (Ibanez-Tallon et al., Neuron, 2002, Tekinay et al., PNAS, 2008), and modifies nicotine response properties (Miwa et al., 2006). Therefore amino acid sequence differences in lynx2 may alter the affinity of the lynx/nicotinic receptors interaction and thereby influence the overall tone these receptors impart to the amygdala. We have also aimed to characterize single nucleotide polymorphisms (SNPs) in lynx2 in humans in order to understand how these genes regulate anxiety levels. Isolation of the lynx genes from participant samples revealed the presence of several SNPs, which results in structural abnormalities in loops of the lynx2 protein. We want to test the hypothesis, by assaying the relevant mutations functionally. We aim to produce the protein and SNP variants of the protein, and test them through atomic force microscopy measurements (AFM). The preliminary results from the collaboration with the Zhang lab are promising in that we can express and detect lynx2 protein. Our initial studies piloted in last year’s BDSI, demonstrate that it is possible to detect binding of lynx proteins using AFM measurements of cells containing nicotinic receptors. These studies could provide a critical causal link between lynx2, nAChRs and anxiety regulation, which could have a beneficial impact on our understanding of anxiety disorders.