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Cell-type-specific disruption of PERK-eIF2α signaling in dopaminergic neurons alters motor and cognitive function

Abstract

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) has been shown to activate the eIF2α kinase PERK to directly regulate translation initiation. Tight control of PERK-eIF2α signaling has been shown to be necessary for normal long-lasting synaptic plasticity and cognitive function, including memory. In contrast, chronic activation of PERK-eIF2α signaling has been shown to contribute to pathophysiology, including memory impairments, associated with multiple neurological diseases, making this pathway an attractive therapeutic target. Herein, using multiple genetic approaches we show that selective deletion of the PERK in mouse midbrain dopaminergic (DA) neurons results in multiple cognitive and motor phenotypes. Conditional expression of phospho-mutant eIF2α in DA neurons recapitulated the phenotypes caused by deletion of PERK, consistent with a causal role of decreased eIF2α phosphorylation for these phenotypes. In addition, deletion of PERK in DA neurons resulted in altered de novo translation, as well as changes in axonal DA release and uptake in the striatum that mirror the pattern of motor changes observed. Taken together, our findings show that proper regulation of PERK-eIF2α signaling in DA neurons is required for normal cognitive and motor function in a non-pathological state, and also provide new insight concerning the onset of neuropsychiatric disorders that accompany UPR failure.

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Fig. 1: Deletion of PERK from DA neurons induces motor facilitation, but results in multiple cognitive phenotypes and dysregulated de novo translation in mice.
Fig. 2: eIF2α(S51A/S51A) DAT-Cre mice display enhanced locomotor activity.
Fig. 3: eIF2α(S51A/S51A) DAT-Cre mice display multiple cognitive phenotypes.
Fig. 4: Deletion of PERK in DA neurons alters striatal DA release and DAT activity in mice.
Fig. 5: Selective virogenetic deletion of PERK in DA neurons of the SNc or the VTA results in motor or cognitive phenotypes, respectively similar to those displayed by the PERKf/f DAT-Cre mice.

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Data availability

The data that support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

We thank Dr Caroline Bass (University at Buffalo) for providing the AAV2/10-TH-iCre and AAV2/10-TH-dsRED adeno-associated viruses and Dr Randal Kaufman (Sanford Burnham Prebys Medical Discovery Institute) for providing the Eif2(S51A) mouse line; We wish to acknowledge Claudia Farb for exceptional technical assistance and Dr Prerana Shrestha for critical advice and review of this paper. We thank all members of the Klann laboratory for critical feedback and discussions. The MATLAB script for Vmax analysis was written and provided by Dr Charles Nicholson at NYU Grossman School of Medicine. This study was supported by National Institutes of Health Grants NS034007 and NS047384 (EK), DA038616 (MER), U.S. Department of Defense Award W81XWH-15-1-0360 (EK), and the Marlene and Paolo Fresco Institute for Parkinson’s Disease and Movement Disorders (MM and MER).

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FL carried out the behavioral experiments, performed slice electrophysiology experiments, and collected and analyzed all in vivo and ex vivo data. MM carried out and analyzed the FSCV experiments. SA carried out western blotting and collected ex vivo data. PLI and CM carried out behavioral experiments and collected in vivo and ex vivo data. JCP performed DAT-mediated dopamine uptake analysis. MER coordinated, performed, and analyzed HPLC experiments. EP and NR carried out HPLC experiments. MD performed genotyping of the mice. FL, EK, ES conceived the studies. MM and MER participated in the design of the studies. FL and EK designed and coordinated all experiments and wrote the paper. All authors read and commented on the paper.

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Correspondence to Eric Klann.

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Longo, F., Mancini, M., Ibraheem, P.L. et al. Cell-type-specific disruption of PERK-eIF2α signaling in dopaminergic neurons alters motor and cognitive function. Mol Psychiatry 26, 6427–6450 (2021). https://doi.org/10.1038/s41380-021-01099-w

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