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GSK3?, not GSK3?, drives hippocampal NMDAR-dependent LTD via tau-mediated spine anchoring

ABSTRACT: Glycogen synthase kinase-3 (GSK3) is an important signaling protein in the brain and modulates different forms of synaptic plasticity. Neuronal functions of GSK3 are typically attributed to one of its two isoforms, GSK3?, simply because of its prevalent expression in the brain. Consequently, the importance of isoform-specific functions of GSK3 in synaptic plasticity has not been fully explored. We now directly address this question for NMDA receptor-dependent long-term depression (LTD) in the hippocampus. Here, we specifically target the GSK3 isoforms with shRNA knockdown in mouse hippocampus and with novel isoform-selective drugs to dissect their roles in LTD. Using electrophysiological and live imaging approaches, we find that GSK3?, but not GSK3?, is required for LTD. The specific engagement of GSK3? occurs via its transient anchoring in dendritic spines during LTD induction. We find that the major GSK3 substrate, the microtubule-binding protein tau, is required for this spine anchoring of GSK3? and mediates GSK3?-induced LTD. These results link GSK3? and tau in a common mechanism for synaptic depression and rule out a major role for GSK3? in this process.

SUBMITTER: Jonathan, E Draffin

PROVIDER: S-SCDT-EMBOJ-2020-105513 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:In Alzheimer's disease (AD), dysregulation of intracellular Ca2+ signalling has been observed as an early event prior to the presence of clinical symptoms and is believed to be a crucial factor contributing to AD pathogenesis. Amyloid-? oligomers (A?Os) disturb the N-methyl-D-aspartate receptor (NMDAR)-mediated postsynaptic Ca2+ signalling in response to presynaptic stimulation by increasing the availability of extracellular glutamate as well as directly disturbing the NMDARs. The abnormal Ca2+ response can further lead to impairments in long-term potentiation (LTP), an important process in memory formation. In this study, we develop a mathematical model of a CA1 pyramidal dendritic spine and conduct computational experiments. We use this model to mimic alterations by A?Os under AD conditions to investigate how they are involved in the Ca2+ dysregulation in the dendritic spine. The alterations in glutamate availability, as well as NMDAR availability and activity, are studied both individually and globally. The simulation results suggest that alterations in glutamate availability mostly affect the synaptic response and have limited effects on the extrasynaptic receptors. Moreover, overactivation of extrasynaptic NMDARs in AD is unlikely to be induced by presynaptic stimulation, but by upregulation of the resting level of glutamate, possibly resulting from these alterations. Furthermore, internalisation of synaptic NR2A-NMDAR shows greater damage to the postsynaptic Ca2+ response in comparison with the internalisation of NR2B-NMDARs; thus, the suggested neuroprotective role of the latter is very limited during synaptic transmission in AD. We integrate a CaMKII state transition model with the Ca2+ model to further study the effects of alterations of NMDARs in the CaMKII state transition, an important downstream event in the early phase of LTP. The model reveals that cooperation between NR2A- and NR2B-NMDAR is required for LTP induction. Under AD conditions, internalisation of membrane NMDARs is suggested to be the cause of the loss of synapse numbers by disrupting CaMKII-NMDAR formation.

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GSK3?, not GSK3?, drives hippocampal NMDAR-dependent LTD via tau-mediated spine anchoring

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