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Activation of D2-like dopamine receptors improves the neuronal network and cognitive function of PPT1KI mice

Acta Pharmacologica Sinica volume 46, pages 338–352 (2025)Cite this article

Abstract

Palmitoyl-protein thioesterase 1 (PPT1) is a lysosomal depalmitoylation enzyme that mediates protein posttranslational modifications. Loss-of-function mutation of PPT1 causes a failure of the lysosomal degradation of palmitoylated proteins and results in a congenital disease characterized by progressive neuronal degeneration referred to as infantile neuronal ceroid lipofuscinosis (INCL). A mouse knock-in model of PPT1 (PPT1-KI) was established by introducing the R151X mutation into exon 5 of the PPT1 gene, which exhibited INCL-like pathological lesions. We previously reported that hippocampal γ oscillations were impaired in PPT1 mice. Hippocampal γ oscillations can be enhanced by selective activation of the dopamine D4 receptor (DR4), a dopamine D2-like receptor. In this study, we investigated the changes in DR expression and the effects of dopamine and various DR agonists on neural network activity, cognition and motor function in PPT1KI mice. Cognition and motor defects were evaluated via Y-maze, novel object recognition and rotarod tests. Extracellular field potentials were elicited in hippocampal slices, and neuronal network oscillations in the gamma frequency band (γ oscillations) were induced by perfusion with kainic acid (200 nM). PPT1KI mice displayed progressive impairments in γ oscillations and hippocampus-related memory, as well as abnormal expression profiles of dopamine receptors with preserved expression of DR1 and 3, increased membrane expression of DR4 and decreased DR2 levels. The immunocytochemistry analysis revealed the colocalization of PPT1 with DR4 or DR2 in the soma and large dendrites of both WT and PPT1KI mice. Immunoprecipitation confirmed the interaction between PPT1 and DR4 or DR2. The impaired γ oscillations and cognitive functions were largely restored by the application of exogenous dopamine, the selective DR2 agonist quinpirole or the DR4 agonist A412997. Furthermore, the administration of A412997 (0.5 mg/kg, i.p.) significantly upregulated the activity of CaMKII in the hippocampus of 5-month-old PPT1KI mice. Collectively, these results suggest that the activation of D2-like dopamine receptors improves cognition and network activity in PPT1KI mice and that specific DR subunits may be potential targets for the intervention of neurodegenerative disorders, such as INCL.

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Fig. 1: Impaired memory and locomotor function in PPT1 mice.
Fig. 2: Impaired hippocampal γ oscillations in PPT1 mice.
Fig. 3: Effects of dopamine and DR1 agonists on γ oscillations in WT and PPT1KI mice.
Fig. 4: Effects of DR2 and DR4 agonists on γ oscillations in WT and PPT1KI mice.
Fig. 5: Expression of DR subunits in the hippocampal tissues of WT and PPT1KI mice.
Fig. 6: Expression and localization of PPT1, DRD4 and DRD2 in primary cultured hippocampal neurons.
Fig. 7: Expression of CaMKII and p-CaMKIIα in the hippocampal tissues from WT and PPT1KI mice.
Fig. 8: The DR4 agonist A412997 improved the behavior of PPT1KI mice.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (NSFC: 81771517; 81271422); the Key Project of the 14th Five-Year Plan of Educational Science in Henan Province (2021JKZD09); the Key Scientific and Technological Project in Henan Province (212102310654); the Henan Province Medical Science and Technology Key Project Jointly Constructed by Province and Ministry (SBGJ202102189); the Key R&D and Promotion Projects in Henan Province (222102310615); Natural Science Foundation of Henan Province (242300421307); the Tai-hang Scholar Research Fund from Xinxiang Medical University; and the Henan Collaborative Innovation Center of Prevention and Treatment of Mental Disorders, the Second Affiliated Hospital of Xinxiang Medical University (XTkf11).

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  1. These authors contributed equally: Jun-qiang Zhao, Bing-yan Feng

Authors and Affiliations

  1. First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 435000, China

    Jun-qiang Zhao, Bing-yan Feng, Wan-liu Wu & Cheng-biao Lu

  2. School of Medical Imaging, Xinxiang Medical University, Xinxiang, 435000, China

    Jun-qiang Zhao

  3. Henan International Joint Laboratory for Noninvasive Neuromodulation/Key Laboratory of Brain Research of Henan Province, Department of Physiology & Pathophysiology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, 435000, China

    Zhen-li Ye, Xiao-yin Ma, Shi-yong Peng, Ji-sen Huai, Li-hao Ge & Cheng-biao Lu

  4. Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, 435000, China

    Jing-zhi Du, Jun-mei Li, Jing-jing Gao, Song-ji Li & Cheng-biao Lu

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Contributions

CBL designed and supervised the research; JQZ, BYF, ZLY and XYM performed the field recordings, Western blots and behavioral studies; JML, WLW, JJG, and JZD performed the cell culture, Western blots, ICC and ABE experiments; CBL, JQZ, SJL, SYP and JSH analyzed the data; and CBL, LHG and BYF wrote and revised the paper.

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Correspondence to Li-hao Ge or Cheng-biao Lu.

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Zhao, Jq., Feng, By., Ye, Zl. et al. Activation of D2-like dopamine receptors improves the neuronal network and cognitive function of PPT1KI mice. Acta Pharmacol Sin 46, 338–352 (2025). https://doi.org/10.1038/s41401-024-01377-7

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