Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: role of endogenous acetylcholine

Caspases are a family of conserved cysteine proteases that play key roles in multiple cellular processes, including programmed cell death and inflammation. Recent evidence shows that caspases are also involved in crucial non-apoptotic functions, such as dendrite development, axon pruning, and synaptic plasticity mechanisms underlying learning and memory processes. The activated form of caspase-3, which is known to trigger widespread damage and degeneration, can also modulate synaptic function in the adult brain. Thus, in the present study, we tested the hypothesis that caspase-3 modulates synaptic plasticity at corticostriatal synapses in the phosphatase and tensin homolog (PTEN) induced kinase 1 (PINK1) mouse model of Parkinson’s disease (PD). Loss of PINK1 has been previously associated with an impairment of corticostriatal long-term depression (LTD), rescued by amphetamine-induced dopamine release. Here, we show that caspase-3 activity, measured after LTD induction, is significantly decreased in the PINK1 knockout model compared with wild-type mice. Accordingly, pretreatment of striatal slices with the caspase-3 activator α-(Trichloromethyl)-4-pyridineethanol (PETCM) rescues a physiological LTD in PINK1 knockout mice. Furthermore, the inhibition of caspase-3 prevents the amphetamine-induced rescue of LTD in the same model. Our data support a hormesis-based double role of caspase-3; when massively activated, it induces apoptosis, while at lower level of activation, it modulates physiological phenomena, like the expression of corticostriatal LTD. Exploring the non-apoptotic activation of caspase-3 may contribute to clarify the mechanisms involved in synaptic failure in PD, as well as in view of new potential pharmacological targets.

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Inhibition of Endoplasmic Reticulum Stress Reverses Synaptic Plasticity Deficits in Striatum of DYT1 Dystonia Mice

10.21203/rs.3.rs-166434/v1 ◽

2021 ◽

Author(s):

Huaying Cai ◽

Linhui Ni ◽

Xingyue Hu ◽

Xianjun Ding

Keyword(s):

Endoplasmic Reticulum ◽

Synaptic Plasticity ◽

Er Stress ◽

Critical Role ◽

Stress Protein ◽

Long Term Potentiation ◽

Research Field ◽

Protein Levels ◽

Dyt1 Dystonia

Abstract Background & objectiveStriatal plasticity alterations caused by endoplasmic reticulum (ER) stress is supposed to be critically involved in the mechanism of DYT1 dystonia. In the current study, we expanded this research field by investigating the critical role of ER stress underlying synaptic plasticity impairment imposed by mutant heterozygous Tor1a+/- in a DYT1 dystonia mouse model.Methods & resultsLong-term depression (LTD) was failed to be induced, while long-term potentiation (LTP) was further strengthened in striatal spiny neurons (SPNs) from the Tor1a+/- DYT1 dystonia mice. Spine morphology analyses revealed a significant increase of both number of mushroom type spines and spine width in Tor1a+/- SPNs. In addition, increased AMPA receptor function and the reduction of NMDA/AMPA ratio in the postsynaptic of Tor1a+/- SPNs was observed, along with increased ER stress protein levels in Tor1a+/- striatum. Notably, ER stress inhibitors, tauroursodeoxycholic acid (TUDCA), could rescue LTD as well as AMPA currents.ConclusionThe current study illustrated the role of ER stress in mediating structural and functional plasticity alterations in Tor1a+/- SPNs. Inhibition of the ER stress by TUDCA is beneficial in reversing the deficits at the cellular and molecular levels. Remedy of dystonia associated neurological and motor functional impairment by ER stress inhibitors could be a recommendable therapeutic agent in clinical practice.

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Extrasynaptic CaMKIIα is involved in the antidepressant effects of ketamine by downregulating GluN2B receptors in an LPS-induced depression model

10.21203/rs.2.22906/v1 ◽

2020 ◽

Author(s):

Xiao-Hui Tang ◽

Guang-Fen Zhang ◽

Ning Xu ◽

Gui-Fang Duan ◽

Min Jia ◽

...

Keyword(s):

Synaptic Plasticity ◽

Mouse Model ◽

Cellular Mechanism ◽

Antidepressant Effect ◽

Immunoprecipitation Assay ◽

Antidepressant Effects ◽

High Level ◽

Induced Changes ◽

The Relationship

Abstract Background A subanesthetic dose of ketamine provides rapid and effective antidepressant effects, but the molecular mechanism of this treatment remains elusive. Methods In this study, we investigated the role of CaMKIIα in the antidepressant effects of ketamine using an LPS-induced mouse model of depression, explored the different changes of CaMKIIα in the synaptic and extrasynaptic regions of the hippocampus, and clarified the relationship between CaMKIIα and GluN2B from extrasynaptic perspective. Results Ketamine (10 mg/kg, i.p.) administration attenuated the LPS-induced increase in extrasynaptic CaMKIIα activity (p-CaMKIIα) and extrasynaptic GluN2B localization and phosphorylation and that ketamine exerted antidepressant effects. Immunoprecipitation assay revealed that in the extrasynaptic region of the hippocampus, p-CaMKIIα bound to GluN2B, and ketamine administration attenuated the enhanced interaction between p-CaMKIIα and GluN2B induced by LPS. KN93, a CaMKIIα inhibitor, could also reverse the high level of extrasynaptic p-CaMKIIα, reduce hippocampal extrasynaptic GluN2B localization and phosphorylation, and exert antidepressant effects. Additional changes downstream of the ketamine-induced changes in extrasynaptic GluN2B included rescuing the downregulated expression of p-CREB, BDNF, and GluR1 and reversing the impaired induction of LTP in the hippocampus induced by LPS. Conclusion These results indicate that extrasynaptic CaMKIIα plays a key role in the cellular mechanism of ketamine's antidepressant effect and is related to the down-regulation of extrasynaptic GluN2B localization and phosphorylation and further affects synaptic plasticity.

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