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Selective recognition memory impairment in mitochondrial hydroxylase Clk1 mutant mice, rescued by antipsychotics

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Mitochondria are not only the most important organelles in eukaryotic cells that participate in energy metabolism, signal transduction, cell apoptosis and other physiological processes, but also essential regulators of neurodevelopment, neuroplasticity, survival and adult neurogenesis. The mitochondria-localized hydroxylase Clk-1 is involved in ubiquinone biosynthesis. Recent evidence shows that Clk1+/− mutant mice are resistant to morphine- and methamphetamine-induced conditioned place preference. Given the critical role of learning and memory in drug dependence, we herein explored whether and how Clk1 deficiency affected the cognitive processes in mice. We found that mutant Clk1 mice (Clk1+/−) exhibited recognition memory impairment in novel object recognition (NOR) and novel arm recognition (NAR) tests. In addition, we observed in Clk1+/− mutant mice a selective reduction in dendritic spine density in prefrontal cortex (PFC) but not in the hippocampus (HIP). The expression of brain-derived neurotrophic factor (BDNF) was also decreased in PFC but not in HIP. Furthermore, Clk1+/− mutant mice displayed impairment in the ERK/CREB signaling pathway in PFC that might underlie Clk1+/− mutation-induced changes in BDNF and dendritic morphology. Administration of antipsychotic drugs aripiprazole (0.3 mg·kg−1·d−1, i.p.) or risperidone (1 mg·kg−1·d−1, i.p.) for 7 days fully rescued Clk1 mutation-induced recognition memory deficits. This study provides primary evidence highlighting the role of mitochondrial Clk1 in the regulation of recognition memory and presents an informative model for investigating mitochondrial function in learning and memory.

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Fig. 1: Clk1 deficiency induces recognition memory impairment.
Fig. 2: Clk1 deficiency induces a decrease in dendritic spine density in prefrontal cortex (PFC) but not in hippocampus (HIP).
Fig. 3: Clk1 deficiency results in decreased BDNF expression in PFC.
Fig. 4: Clk1 deficiency attenuates neuronal differentiation of PC12 cells and axonal development of primary cortical neurons in Clk1+/− mutant mice.
Fig. 5: Clk1 deficiency attenuates activation of the ERK/CREB pathway.
Fig. 6: Administration of aripiprazole and risperidone each rescue impaired recognition memory in Clk1+/− mutant mice in the novel arm recognition (NAR) test.
Fig. 7: Schematic overview of impaired recognition memory in Clk1+/− mutant mice.

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References

  1. Goldman JG, Sieg E. Cognitive impairment and dementia in parkinson disease. Clin Geriatr Med. 2020;36:365–77.

    Article  PubMed  Google Scholar 

  2. McCutcheon RA, Keefe RSE, McGuire PK. Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment. Mol Psychiatry. 2023;28:1902–18.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Friedman NP, Robbins TW. The role of prefrontal cortex in cognitive control and executive function. Neuropsychopharmacology. 2022;47:72–89.

    Article  PubMed  Google Scholar 

  4. Arion D, Huo Z, Enwright JF, Corradi JP, Tseng G, Lewis DA. Transcriptome alterations in prefrontal pyramidal cells distinguish schizophrenia from bipolar and major depressive disorders. Biol Psychiatry. 2017;82:594–600.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Yan Z, Rein B. Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications. Mol Psychiatry. 2022;27:445–65.

    Article  PubMed  Google Scholar 

  6. Acosta MJ, Vazquez Fonseca L, Desbats MA, Cerqua C, Zordan R, Trevisson E, et al. Coenzyme q biosynthesis in health and disease. Biochim Biophys Acta. 2016;1857:1079–85.

    Article  PubMed  CAS  Google Scholar 

  7. Annesley SJ, Fisher PR. Mitochondria in health and disease. Cells. 2019;8:680.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Nunnari J, Suomalainen A. Mitochondria: In sickness and in health. Cell. 2012;148:1145–59.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Kim Y, Vadodaria KC, Lenkei Z, Kato T, Gage FH, Marchetto MC, et al. Mitochondria, metabolism, and redox mechanisms in psychiatric disorders. Antioxid Redox Signal. 2019;31:275–317.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Khacho M, Harris R, Slack RS. Mitochondria as central regulators of neural stem cell fate and cognitive function. Nat Rev Neurosci. 2019;20:34–48.

    Article  PubMed  CAS  Google Scholar 

  11. Singh A, Kukreti R, Saso L, Kukreti S. Oxidative stress: a key modulator in neurodegenerative diseases. Molecules. 2019;24:1583.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Yan MH, Wang X, Zhu X. Mitochondrial defects and oxidative stress in alzheimer disease and parkinson disease. Free Radic Biol Med. 2013;62:90–101.

    Article  PubMed  CAS  Google Scholar 

  13. Peruzzotti Jametti L, Willis CM, Krzak G, Hamel R, Pirvan L, Ionescu RB, et al. Mitochondrial complex I activity in microglia sustains neuroinflammation. Nature. 2024;628:195–203.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Li Y, Xia X, Wang Y, Zheng JC. Mitochondrial dysfunction in microglia: a novel perspective for pathogenesis of alzheimer’s disease. J Neuroinflammation. 2022;19:248.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Bajwa E, Pointer CB, Klegeris A. The role of mitochondrial damage-associated molecular patterns in chronic neuroinflammation. Mediat Inflamm. 2019;2019:11.

    Article  Google Scholar 

  16. He CH, Xie LX, Allan CM, Tran UC, Clarke CF. Coenzyme q supplementation or over-expression of the yeast coq8 putative kinase stabilizes multi-subunit coq polypeptide complexes in yeast coq null mutants. Biochim Biophys Acta. 2014;1841:630–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Monaghan RM, Barnes RG, Fisher K, Andreou T, Rooney N, Poulin GB, et al. A nuclear role for the respiratory enzyme clk-1 in regulating mitochondrial stress responses and longevity. Nat Cell Biol. 2015;17:782–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Wang Y, Branicky R, Stepanyan Z, Carroll M, Guimond MP, Hihi A, et al. The anti-neurodegeneration drug clioquinol inhibits the aging-associated protein Clk-1. J Biol Chem. 2009;284:314–23.

    Article  PubMed  CAS  Google Scholar 

  19. Zheng H, Lapointe J, Hekimi S. Lifelong protection from global cerebral ischemia and reperfusion in long-lived Mclk1+/- mutants. Exp Neurol. 2010;223:557–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Gu R, Zhang F, Chen G, Han C, Liu J, Ren Z, et al. Clk1 deficiency promotes neuroinflammation and subsequent dopaminergic cell death through regulation of microglial metabolic reprogramming. Brain Behav Immun. 2017;60:206–19.

    Article  PubMed  CAS  Google Scholar 

  21. Yan Q, Han C, Wang G, Waddington JL, Zheng L, Zhen X. Activation of ampk/mtorc1-mediated autophagy by metformin reverses clk1 deficiency-sensitized dopaminergic neuronal death. Mol Pharmacol. 2017;92:640–52.

    Article  PubMed  CAS  Google Scholar 

  22. Yan PJ, Ren ZX, Shi ZF, Wan CL, Han CJ, Zhu LS, et al. Dysregulation of iron homeostasis and methamphetamine reward behaviors in clk1-deficient mice. Acta Pharmacol Sin. 2022;43:1686–98.

    Article  PubMed  CAS  Google Scholar 

  23. Rogoz Z, Wasik A, Lorenc-Koci E. Combined treatment with aripiprazole and antidepressants reversed some MK-801-induced schizophrenia-like symptoms in mice. Pharmacol Rep. 2018;70:623–30.

    Article  PubMed  CAS  Google Scholar 

  24. Wu L, Feng X, Li T, Sun B, Khan MZ, He L. Risperidone ameliorated Abeta(1-42)-induced cognitive and hippocampal synaptic impairments in mice. Behav Brain Res. 2017;322:145–56.

    Article  PubMed  CAS  Google Scholar 

  25. Lu C, Li S, Kang L, Li Q, Chen H, Lin Y, et al. Aripiprazole combined with nerve growth factor improves cognitive function in mice with schizophrenia model. Neurosci Lett. 2023;812:137410.

    Article  PubMed  CAS  Google Scholar 

  26. Chen J, Li G, Qin P, Chen J, Ye N, Waddington JL, et al. Allosteric modulation of the sigma-1 receptor elicits antipsychotic-like effects. Schizophr Bull. 2022;48:474–84.

    Article  PubMed  Google Scholar 

  27. Wiatrak B, Kubis Kubiak A, Piwowar A, Barg E. PC12 cell line: cell types, coating of culture vessels, differentiation and other culture conditions. Cells. 2020;9:958.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Ren ZX, Zhao YF, Cao T, Zhen XC. Dihydromyricetin protects neurons in an mptp-induced model of Parkinson’s disease by suppressing glycogen synthase kinase-3 beta activity. Acta Pharmacol Sin. 2016;37:1315–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Cryan JF, Markou A, Lucki I. Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci. 2002;23:238–45.

    Article  PubMed  CAS  Google Scholar 

  30. Mouri A, Lee HJ, Mamiya T, Aoyama Y, Matsumoto Y, Kubota H, et al. Hispidulin attenuates the social withdrawal in isolated disrupted-in-schizophrenia-1 mutant and chronic phencyclidine-treated mice. Br J Pharmacol. 2020;177:3210–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Kaminski J, Rutishauser U. Between persistently active and activity-silent frameworks: novel vistas on the cellular basis of working memory. Ann N Y Acad Sci. 2020;1464:64–75.

    Article  PubMed  Google Scholar 

  32. Arion D, Enwright JF 3rd, Gonzalez-Burgos G, Lewis DA. Cell type-specific profiles and developmental trajectories of transcriptomes in primate prefrontal layer 3 pyramidal neurons: implications for schizophrenia. Am J Psychiatry. 2024;181:920–34.

    Article  PubMed  Google Scholar 

  33. Li S, Ma C, Li Y, Chen R, Liu Y, Wan LP, et al. The schizophrenia-associated missense variant rs13107325 regulates dendritic spine density. Transl Psychiatry. 2022;12:361.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Yao W, Zhou P, Yan Q, Wu X, Xia Y, Li W, et al. ERVWE1 reduces hippocampal neuron density and impairs dendritic spine morphology through inhibiting Wnt/JNK non-canonical pathway via miR-141-3p in schizophrenia. Viruses. 2023;15:168.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Kellner Y, Godecke N, Dierkes T, Thieme N, Zagrebelsky M, Korte M. The BDNF effects on dendritic spines of mature hippocampal neurons depend on neuronal activity. Front Synaptic Neurosci. 2014;6:5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Lv J, Lu C, Jiang N, Wang H, Huang H, Chen Y, et al. Protective effect of ginsenoside Rh2 on scopolamine-induced memory deficits through regulation of cholinergic transmission, oxidative stress and the erk-creb-bdnf signaling pathway. Phytother Res. 2021;35:337–45.

    Article  PubMed  CAS  Google Scholar 

  37. Yu X, Guan Q, Wang Y, Shen H, Zhai L, Lu X, et al. Anticonvulsant and anti-apoptosis effects of salvianolic acid B on pentylenetetrazole-kindled rats via Akt/CREB/BDNF signaling. Epilepsy Res. 2019;154:90–6.

    Article  PubMed  CAS  Google Scholar 

  38. Yoshii A, Constantine Paton M. BDNF induces transport of psd-95 to dendrites through pi3k-akt signaling after nmda receptor activation. Nat Neurosci. 2007;10:702–11.

    Article  PubMed  CAS  Google Scholar 

  39. Ray MT, Shannon Weickert C, Webster MJ. Decreased bdnf and trkb mrna expression in multiple cortical areas of patients with schizophrenia and mood disorders. Transl Psychiatry. 2014;4:e389.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Szota AM, Kowalewska B, Cwiklinska Jurkowska M, Drozdz W. The Influence of electroconvulsive therapy (ECT) on brain-derived neurotrophic factor (BDNF) plasma level in patients with schizophrenia-a systematic review and meta-analysis. J Clin Med. 2023;12:5728.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Mohammadi A, Rashidi E, Amooeian VG. Brain, blood, cerebrospinal fluid, and serum biomarkers in schizophrenia. Psychiatry Res. 2018;265:25–38.

    Article  PubMed  CAS  Google Scholar 

  42. Angelucci F, Brene S, Mathe AA. BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry. 2005;10:345–52.

    Article  PubMed  CAS  Google Scholar 

  43. Jin H, Yang C, Jiang C, Li L, Pan M, Li D, et al. Evaluation of neurotoxicity in BALB/c mice following chronic exposure to polystyrene microplastics. Environ Health Perspect. 2022;130:107002.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Luine V, Mohan G, Attalla S, Jacome L, Frankfurt M. Androgens enhance recognition memory and dendritic spine density in the hippocampus and prefrontal cortex of ovariectomized female rats. Neuroscience. 2025;568:465–75.

    Article  PubMed  CAS  Google Scholar 

  45. Diab AM, Wigerius M, Quinn DP, Qi J, Shahin I, Paffile J, et al. Nck1 modulates neuronal actin dynamics and promotes dendritic spine, synapse, and memory formation. J Neurosci. 2023;43:885–901.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Cavalcante LES, Zinn CG, Schmidt SD, Saenger BF, Ferreira FF, Furini CRG, et al. Modulation of the storage of social recognition memory by neurotransmitter systems in the insular cortex. Behav Brain Res. 2017;334:129–34.

    Article  PubMed  CAS  Google Scholar 

  47. Borkar CD, Bharne AP, Nagalakshmi B, Sakharkar AJ, Subhedar NK, Kokare DM. Cocaine- and amphetamine-regulated transcript peptide (CART) alleviates MK-801-induced schizophrenic dementia-like symptoms. Neuroscience. 2018;375:94–107.

    Article  PubMed  CAS  Google Scholar 

  48. Perez Palomar B, Erdozain AM, Erkizia Santamaria I, Ortega JE, Meana JJ. Maternal immune activation induces cortical catecholaminergic hypofunction and cognitive impairments in offspring. J Neuroimmune Pharmacol. 2023;18:348–65.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Steimel SA, Meisenhelter S, Quon RJ, Camp EJ, Tom R, Bujarski KA, et al. Accelerated long-term forgetting of recall and recognition memory in people with epilepsy. Epilepsy Behav. 2023;141:109152.

    Article  PubMed  Google Scholar 

  50. Sanborn V, Putcha D, Tremont G. Correlates of recognition memory performance in amnestic mild cognitive impairment. J Clin Exp Neuropsychol. 2018;40:205–11.

    Article  PubMed  Google Scholar 

  51. Zhang Y, Liu X, Wiggins KL, Kurniansyah N, Guo X, Rodrigue AL, et al. Association of mitochondrial dna copy number with brain mri markers and cognitive function: a meta-analysis of community-based cohorts. Neurology. 2023;100:e1930–e43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Alexander JF, Seua AV, Arroyo LD, Ray PR, Wangzhou A, Heibeta-Luckemann L, et al. Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits. Theranostics. 2021;11:3109–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Hara Y, Yuk F, Puri R, Janssen WG, Rapp PR, Morrison JH. Presynaptic mitochondrial morphology in monkey prefrontal cortex correlates with working memory and is improved with estrogen treatment. Proc Natl Acad Sci USA. 2014;111:486–91.

    Article  PubMed  CAS  Google Scholar 

  54. Picard M, McEwen BS. Mitochondria impact brain function and cognition. Proc Natl Acad Sci USA. 2014;111:7–8.

    Article  PubMed  CAS  Google Scholar 

  55. Cheng J, Yang HL, Gu CJ, Liu YK, Shao J, Zhu R, et al. Melatonin restricts the viability and angiogenesis of vascular endothelial cells by suppressing HIF-1alpha/ROS/VEGF. Int J Mol Med. 2019;43:945–55.

    PubMed  CAS  Google Scholar 

  56. Heroux NA, Horgan CJ, Pinizzotto CC, Rosen JB, Stanton ME. Medial prefrontal and ventral hippocampal contributions to incidental context learning and memory in adolescent rats. Neurobiol Learn Mem. 2019;166:107091.

    Article  PubMed  Google Scholar 

  57. Chao OY, Nikolaus S, Yang YM, Huston JP. Neuronal circuitry for recognition memory of object and place in rodent models. Neurosci Biobehav Rev. 2022;141:104855.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Zarneshan SN, Fakhri S, Khan H. Targeting AKT/CREB/BDNF signaling pathway by ginsenosides in neurodegenerative diseases: a mechanistic approach. Pharmacol Res. 2022;177:106099.

    Article  PubMed  CAS  Google Scholar 

  59. Coley AA, Gao WJ. PSD-95 deficiency disrupts pfc-associated function and behavior during neurodevelopment. Sci Rep. 2019;9:9486.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (2021YFE0206000) and a National Innovation of Science and Technology-2030 (Program of Brain Science and Brain-Inspired Intelligence Technology) Grant (2021ZD0204004). We also acknowledge support from the Suzhou International Academician Work Station and Priority Academic Program Development (PAPD) of the Jiangsu Higher Education Institutes.

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  1. These authors contributed equally: Zhi-feng Shi, Zhe-xiang Yu

Authors and Affiliations

  1. Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China

    Zhi-feng Shi, Zhe-xiang Yu, Ling-han Gu, Zhi-xue Ma, Qin-bo Chen, Li-bin Wen, John L. Waddington & Xue-chu Zhen

  2. School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland

    John L. Waddington

  3. Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, 215123, China

    Xue-chu Zhen

  4. College of Life Science, Suzhou University of Technology, Suzhou, 215123, China

    Xue-chu Zhen

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  1. Zhi-feng Shi
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Contributions

XCZ designed the research. ZFS analyzed the data and drafted the manuscript. ZFS, ZXY and ZXM performed the behavioral, molecular biological and biochemical experiments. QBC, LBW and LHG performed experiments and collected data. JLW and XCZ analyzed and interpreted the data and edited the manuscript. All authors reviewed the manuscript and approved the submission for publication.

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Correspondence to Xue-chu Zhen.

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Shi, Zf., Yu, Zx., Gu, Lh. et al. Selective recognition memory impairment in mitochondrial hydroxylase Clk1 mutant mice, rescued by antipsychotics. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01641-4

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