Biology subjects

Sourander, C.

Publications and source records attributed to Sourander, C..

3 recordsLinked to original sources

bioRxiv2025

Identifying JNK-regulated phosphoproteome markers of anxiety-like behaviour in mouse hippocampus

JNKs mediate neuronal damage in neurodegenerative disease and inhibitors of JNK1 have shown anxiolytic and anti-depressive effects in mice. Here, we analyze the phosphoproteomes of hippocampus and nucleus accumbens from DJNKI-1 (JNK inhibitor)-infused mice. We correlate phospho-site changes with anxiety-like behaviours in the elevated plus maze and light-dark test and identify unique changes in responder mice. Among the DJNKI-1 regulated phosphosites, several lie within GSK3 motifs and are exclusively down-regulated. Consistent with this, GSK3{beta} is inhibited and AKT activated. Importantly, we detect multilevel regulation of glucose metabolism enzymes including increased PDPK1-S241 phosphorylation, and a 5-fold increase in pyruvate dehydrogenase (PDHA1)-S-293 phosphorylation, signifying its inhibition. This suggests that JNK inhibitor drives a metabolic transformation to the neuronal Warburg response. This and a range of identified synaptic and cytoskeletal protein phosphosite changes are discussed in the context of JNK-regulated anxiety responses. The annotated hippocampal and nucleus accumbens phosphoproteomes described here will support a mechanistic understanding of the JNK pathway for future studies of brain disorders.

neuroscience↗

bioRxiv2025

JNK regulates GABAAR expression at the cell surface via the receptor clustering protein GIT1 (ArfGAP1)

GABAA-type receptors (GABAARs) mediate fast and tonic inhibition and are essential for maintaining excitatory/inhibitory balance in neural circuits. Disrupted GABAergic signaling leads to maladaptive changes associated with neuropsychiatric disorders, yet the mechanisms that regulate GABAAR surface availability remain incompletely understood. We previously identified that the stress-activated kinase JNK1 drives anxiety-like behaviours in mice suggesting a potential link between stress signalling and GABAergic regulation. Here, we show that genetic deletion or inhibition of JNK1 increases surface expression of {beta}3-containing GABAARs at extrasynaptic sites and at excitatory synapses where they may participate in shunting inhibition. We identify the signalling scaffold GIT1 as a direct JNK1 substrate, phosphorylated at S371, and find that GIT1 accumulates in dendritic spines in Jnk1-/- neurons or following JNK inhibition, whereas the phosphomimetic GIT1-S371D is excluded. Moreover, GIT1 is required for JNK-dependent regulation of {beta}3-GABAAR trafficking. Accordingly, neurons from Jnk1-/- mice exhibit increased spontaneous inhibitory postsynaptic potentials and enhanced tonic inhibition. These results reveal a JNK1-GIT1 signalling axis that suppresses GABAAR stability and inhibitory tone, providing a mechanism by which the stress-activated JNK pathway modulates synaptic and extrasynaptic inhibition.

neuroscience↗

bioRxiv2024

JNK1 And Downstream Signalling Hubs Regulate Anxiety-Like Behaviours In A Zebrafish Larvae Phenotypic Screen

Current treatments for anxiety and depression show limited efficacy in many patients indicating that research into new underlying mechanisms is needed. Inhibition of JNK1 has been shown to evoke an anxiolytic-and antidepressant-like phenotype in mice however the downstream effectors that elicit these behavioural effects are unknown. Here we employ a zebrafish (D. Rerio) larvae behavioural assay to identify an antidepressant-/anxiolytic-like phenotype based on 2759 measured stereotypic responses to clinically proven antidepressant and anxiolytic (AA) drugs. Employing machine learning, we classify an AA phenotype from behavioural features measured during and after a startle battery in fish exposed to AA drugs (fluoxetine, imipramine, diazepam, lithium chloride, ketamine). We demonstrate that structurally independent JNK inhibitors replicate the AA classification with high accuracy, consistent with findings in mice. We go on to identify signalling hubs downstream from JNK1 by comparing phosphoproteome data from wildtype and Jnk1-/- mouse brains, and test these hubs as possible mediators of the AA phenotype in zebrafish larvae. Among these, we find that AKT, GSK-3, 14-3-3{zeta}/{varepsilon} and PKC{varepsilon}, when pharmacologically targeted, phenocopy clinically proven AA drugs. This assay shows promise as an early phase screening for compounds with anti-stress-axis/anxiolytic-like properties, and for mode of action analysis.

pharmacology and toxicology↗