Identifying the Effect of JNK on Neural Activity and Synaptic Plasticity Related to Anxiety- and Depressive-like Behaviours

Depressive and anxiety disorders are a problem worldwide, with a complex aetiology, treatments having only limited efficacy, and many patients are never cured. Many of the underlying cellular and molecular processes have yet to be understood. The stress-activated protein C-Jun N-terminal kinase, JNK, has high activity in the brain, where it regulates neuroplasticity and has been shown to impact depressive and anxiety-like behaviours in mice. Many of the specific mechanisms and downstream effectors of JNK remain to be elucidated, however.

For this purpose, the author mainly used primary neuronal cultures in conjunction with fluorescent reporters and immunoblotting to investigate calcium and voltage dynamics and JNK regulated proteins, as well as zebrafish larvae to characterise and utilise a screen based on their behavioural phenotypes. This was done for studies that also used phosphoproteomics, bioinformatics, immunohistochemistry, and animal experiments to analyse neuronal cultures and slices, brain tissue, and live rodents.

JNK was found to regulate spine morphology equilibrium, calcium and voltage dynamics, and ß3-containing GABA_AR complex stability and function. An assay for compounds with anxiolytic-like effect was established, and phosphosite changes relevant for psychiatric disease in brain upon JNK genetic deletion and in hippocampus and nucleus accumbens with pharmacological inhibition were discovered.  Functions for DCX, AKT, GSK-3β, 14-3-3, GIT1 and GABA_AR ß3 as downstream effectors of JNK were established.

This thesis helps elucidate our understanding of JNK and its downstream effectors and how they relate to anxiety-like behaviours. Thereby it explores the underlying molecular processes of maladaptive neuroplasticity and neuronal physiology in mental disorders.