Reversing anxiety by targeting a stress-responsive signaling pathway

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Current anxiety and depressive disorder treatments have significant side effects and limited efficacy.
• There is a critical need for novel molecular targets to develop improved medications.

Purpose of the Study:

• To identify a molecular cascade triggered by chronic stress that exacerbates anxiety- and depressive-like behaviors.
• To investigate the potential of targeting this cascade for therapeutic intervention.

Main Methods:

• Induction of chronic stress in mice to model anxiety and depressive disorders.
• Analysis of Src kinase activity, calmodulin phosphorylation, and MyosinVa (MyoVa) interaction with Neuroligin2 (NL2).
• Pharmacological inhibition of Src kinase and assessment of behavioral and synaptic changes.

Main Results:

• Chronic stress increases Src kinase activity and calmodulin tyrosine phosphorylation.
• This leads to reduced MyoVa-NL2 interaction, decreased inhibitory transmission, and heightened anxiety-like behaviors.
• Pharmacological Src inhibition reverses these synaptic deficits and anxiety-like behaviors, dependent on the MyoVa-NL2 interaction.

Conclusions:

• A molecular cascade involving Src, calmodulin, MyoVa, and NL2 mediates stress-induced anxiety and depressive behaviors.
• The identified molecular and behavioral phenotypes are reversible.
• Src kinase represents a promising therapeutic target for anxiety and depressive disorders.