Paralog-specific roles of GSK-3 in synaptic plasticity and behaviour in the adult mouse hippocampus
Year: 2026
Type: dissertation
Abstract: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that regulates many cellular functions. In the brain, GSK-3 is strongly implicated in several different neurological disorders such as Alzheimer’s disease, bipolar disorders and depression, hence it has gained attention as a potential therapeutic target. GSK-3 is known to play an important role in synaptic plasticity, the process by which neurons change the strength of their synaptic connections. GSK-3 exists as two paralogs, GSK-3α and GSK-3β. The specific contributions of the different paralogs in synaptic plasticity, behaviour and molecular features in the adult brain requires further study. The central question addressed in this thesis is how these paralogs have different roles in regulating synaptic function and how this is linked to their behavioural and molecular characteristics.To address this question, I used mouse models with postnatal conditional deletion of either GSK-3α or GSK-3β in forebrain excitatory neurons, together with paralog-selective inhibitors in adult wild-type mice combined with behavioural testing, electrophysiology recording and biochemical analysis. Behaviourally, deletion of either GSK-3 paralog reduced anxiety levels and improved performance on an executive function task. Whereas, deletion of GSK-3β selectively impaired recognition memory, indicating overlapping but dissociable effects on behavioural domains. With electrophysiological examination, deletion of GSK-3β increased presynaptic release probability without altering basal postsynaptic receptor function in Schaffer-collateral pathways in the hippocampus. Both paralogs were required for metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD), but not N-methyl-D-aspartate receptor dependent long-term depression (NMDA-LTD). Both genetic deletion and pharmacological inhibition of GSK-3α facilitated a protein synthesis-dependent spaced-theta burst induced form of long-term potentiation (sTBS-LTP), while inhibition of GSK-3β had little effect, suggesting that GSK-3α primarily limits persistent synaptic strengthening. Biochemical studies showed paralog-specific profiles of GSK-3 in the brain. Conditional deletion of GSK-3β reduced tau Ser396 phosphorylation, whereas deletion of GSK-3α increased GluA1 Ser845 phosphorylation. In silico prediction and subcellular fractionation showed that GSK-3β is relatively enriched in synaptic and nuclear fractions, while GSK-3α is comparatively depleted from synaptic compartments, indicating paralog-specific compartmentalisation of GSK-3 in the hippocampus. Together, these findings suggest a model in which both paralogs are required for robust mGluR-LTD in the adult hippocampus, with GSK-3β primarily regulating presynaptic release, tau phosphorylation and recognition memory, and GSK-3α preferentially regulating GluA1 phosphorylation, limiting protein-synthesis dependent LTP and contributing to the tuning of anxiety and executive functions. Overall, this PhD thesis highlights the functional importance of paralog-specific organisation of GSK-3 signalling in the adult hippocampus.
Source: TSpace (University of Toronto)
Author: Kang, Shinwon
Institution: University of Toronto
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7204021125