Altering the Stress Response To Reduce Anxiety
Post by Annie Phan
The takeaway
The most common mental health disorders, anxiety and depression, are linked to chronic stress. To design better pharmacological treatments for stress-related disorders, it is important to identify and undo the disruption of chemical interactions in the brain that occur with repeated exposure to stress.
What's the science?
Current medications for anxiety and depressive disorders target related neurotransmitter systems, like serotonin, to yield therapeutic effects. However, they also have side effects that may reflect biological processes unrelated to these disorders. This week in PNAS, Pandey and colleagues used mouse models of chronic stress to investigate signaling pathways that were changed in response to stress manipulation. Then, they attempted to reverse the anxiety behavior by pharmacologically repairing this pathway.
How did they do it?
The researchers used a mouse model of chronic stress where they physically restrained young adult mice for 3 hours daily for 14 consecutive days. They also validated their results with a second mouse model of stress, maternal separation, where young pups from postnatal day 5 to 21 were isolated from their mother for 3 hours daily. To assess the mice for anxiety- and depressive-like behaviours, they used common rodent assays like the elevated plus maze, marble burying test, and forced swim test. To study the molecular events in the brain specifically related to the synapse, they performed biochemical tests to evaluate the amount of relevant proteins and electrophysiological tests to evaluate excitatory and inhibitory transmission. To further investigate the reduction of protein expression, they performed a proteomic screen by co-immunoprecipitation and then mass spectrometry analysis, providing insight into how these proteins interact as part of a signaling pathway.
What did they find?
First, the researchers found that following the chronic stress protocol, the mice in both chronic stress models showed anxiety and depressive-like behavior, and this was in parallel with the decrease in several inhibitory proteins at the synapse including Neuroligin2 (NL2). When they investigated the decrease in NL2 expression further, they found that upregulation of proteins including Src kinase and calmodulin (CaM) resulted in reduced interaction between MyosinVa (MyoVa) and NL2, indicating this pathway was altered in response to chronic stress. The authors manipulated this pathway by suppressing Src kinase activity via an injection of a Src kinase inhibitor, PP2 for 7 consecutive days after the chronic stress protocol. An inactive analog PP3 was used as a control. They observed a reduction in anxiety-like behavior in mice treated with PP2. Overall, inhibiting the elevated activity of Src kinase in chronically stressed mice re-established the expression of synaptic protein NL2 — which was previously reduced by stress — thereby restoring inhibitory synaptic transmission.
What's the impact?
The public health burden of anxiety and depression calls for the need to create more effective and well-tolerated medication for these disorders. This study found a novel therapeutic target sensitive to the stress response, the Src-CaM-MyoVA-NL2 pathway, which is related to the GABA system responsible for inhibitory transmission. Targeting this pathway could help reduce anxiety behavior and improve outcomes for those affected. Further research in humans is needed to validate these findings and explore whether therapies targeting this pathway might be effective.