Skip to main content

Advertisement

SpringerLink
Log in

Rnf-213 Knockout Induces Pericyte Reduction and Blood-Brain Barrier Impairment in Mouse

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by progressive occlusion of the internal carotid artery and the formation of an abnormal compensatory capillary network at the base of the brain. Genomics studies identified Ring finger protein 213 (RNF213) as a common genetic factor that increases the susceptibility to MMD in East Asian people. However, the function of RNF213 and its roles in pathogenesis of MMD is unclear. Here, we showed that genetic knockout of Rnf213 in mice causes significant pericyte reduction and blood-brain barrier impairment in the cortex. These phenotypes are accompanied with microglia activation and elevated level of proinflammatory cytokines. Additionally, Rnf213-deficient mice showed reduced expression of tight junction proteins, including Occludin, Claudin-5, and ZO-1. Together, these data suggested that RNF213 might contribute to the pathogenesis of MMD through disruption of pericyte homeostasis and blood-brain barrier integrity by dysregulation of inflammatory responses and tight junction formation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

MMD:

Moyamoya disease

BBB:

Blood-brain barrier

PDGF-BB:

Platelet-derived growth factor B

PDGFR-β:

Platelet-derived growth factor receptor beta

CCMs:

Cerebral cavernous malformations

WT:

Wild type

EBD:

Evans blue dye

SDS-PAGE:

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis

MMP-9:

Matrix metalloproteinase 9

RNF213:

Ring finger protein 213

CNS:

Central nervous system

NVU:

Neurovascular unit

P2:

2-Day postnatal

PBS:

Phosphate buffer saline

References

  1. Kuroda S, Houkin K (2008) Moyamoya disease: current concepts and future perspectives. Lancet Neurol 7(11):1056–1066. https://doi.org/10.1016/S1474-4422(08)70240-0

    Article  PubMed  Google Scholar 

  2. Scott RM, Smith ER (2009) Moyamoya disease and moyamoya syndrome. N Engl J Med X 360(12):1226–1237. https://doi.org/10.1056/NEJMra0804622

    Article  CAS  Google Scholar 

  3. Ihara M, Yamamoto Y, Hattori Y et al (2022) Moyamoya disease: diagnosis and interventions. Lancet Neurol 21(8):747–758. https://doi.org/10.1016/S1474-4422(22)00165-X

    Article  CAS  PubMed  Google Scholar 

  4. Suzuki J, Takaku A (1969) Cerebrovascular “moyamoya” disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol 20(3):288–99. https://doi.org/10.1001/archneur.1969.00480090076012

    Article  CAS  PubMed  Google Scholar 

  5. Yamashita M, Oka K, Tanaka K (1983) Histopathology of the brain vascular network in moyamoya disease. Stroke 14(1):50–58. https://doi.org/10.1161/01.str.14.1.50

    Article  CAS  PubMed  Google Scholar 

  6. Kamada F, Aoki Y, Narisawa A et al (2011) A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. J Hum Genet 56(1):34–40. https://doi.org/10.1038/jhg.2010.132

    Article  CAS  PubMed  Google Scholar 

  7. Koizumi A, Kobayashi H, Hitomi T, Harada KH, Habu T, Youssefian S (2016) A new horizon of moyamoya disease and associated health risks explored through RNF213. Environ Health Prev Med 21(2):55–70. https://doi.org/10.1007/s12199-015-0498-7

    Article  CAS  PubMed  Google Scholar 

  8. Scholz B, Korn C, Wojtarowicz J et al (2016) Endothelial RSPO3 controls vascular stability and pruning through non-canonical WNT/Ca(2+)/NFAT signaling. Dev Cell 36(1):79–93. https://doi.org/10.7554/eLife.56185

    Article  CAS  PubMed  Google Scholar 

  9. Ahel J, Lehner A, Vogel A, Schleiffer A, Meinhart A, Haselbach D, Clausen T (2020) Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism. Elife 9:e56185. https://doi.org/10.1016/j.devcel.2015.12.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lin J, Liang J, Wen J et al (2021) Mutations of RNF213 are responsible for sporadic cerebral cavernous malformation and lead to a mulberry-like cluster in zebrafish. J Cereb Blood Flow Metab 41(6):1251–1263. https://doi.org/10.1177/0271678X20914996

    Article  CAS  PubMed  Google Scholar 

  11. Sonobe S, Fujimura M, Niizuma K et al (2014) Temporal profile of the vascular anatomy evaluated by 9.4-T magnetic resonance angiography and histopathological analysis in mice lacking RNF213: a susceptibility gene for moyamoya disease. Brain Res 1552:64–71. https://doi.org/10.1016/j.brainres.2014.01.011

    Article  CAS  PubMed  Google Scholar 

  12. Kanoke A, Fujimura M, Niizuma K et al (2015) Temporal profile of the vascular anatomy evaluated by 9.4-tesla magnetic resonance angiography and histological analysis in mice with the R4859K mutation of RNF213, the susceptibility gene for moyamoya disease. Brain Res 1624:497–505. https://doi.org/10.1016/j.brainres.2015.07.039

    Article  CAS  PubMed  Google Scholar 

  13. Ito A, Fujimura M, Niizuma K et al (2015) Enhanced post-ischemic angiogenesis in mice lacking RNF213; a susceptibility gene for moyamoya disease. Brain Res 1594:310–320. https://doi.org/10.1016/j.brainres.2014.11.014

    Article  CAS  PubMed  Google Scholar 

  14. Langen UH, Ayloo S, Gu CH (2019) Development and cell biology of the blood-brain barrier. Annu Rev Cell Dev Biol 35:591–613. https://doi.org/10.1146/annurev-cellbio-100617-062608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV (2019) Blood-brain barrier: from physiology to disease and back. Physiol Rev 99(1):21–78. https://doi.org/10.1152/physrev.00050.2017

    Article  CAS  PubMed  Google Scholar 

  16. Zlokovic BV (2011) Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci 12(12):723–738. https://doi.org/10.1038/nrn3114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV (2015) Establishment and dysfunction of the blood-brain barrier. Cell 163(5):1064–1078. https://doi.org/10.1016/j.cell.2015.10.067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liebner S, Dijkhuizen RM, Reiss Y, Plate KH, Agalliu D, Constantin G (2018) Functional morphology of the blood-brain barrier in health and disease. Acta Neuropathol 135(3):311–336. https://doi.org/10.1007/s00401-018-1815-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ren X, Yao LL, Pan JX, Zhang JS, Mei L, Wang YG, Xiong WC (2021) Linking cortical astrocytic neogenin deficiency to the development of moyamoya disease-like vasculopathy. Neurobiol Dis 154:105339. https://doi.org/10.1016/j.nbd.2021.105339

    Article  CAS  PubMed  Google Scholar 

  20. Lu XC, Huang YB, Zhou P, Hui PJ, Wang Z (2020) Decreased cortical perfusion in areas with blood-brain barrier dysfunction in Moyamoya disease. Acta Neurochir (Wien) 162(10):2565–2572. https://doi.org/10.1007/s00701-020-04480-w

    Article  PubMed  Google Scholar 

  21. Narducci A, Yasuyuki K, Onken J, Blecharz K, Vajkoczy P (2019) In vivo demonstration of blood-brain barrier impairment in moyamoya disease. Acta Neurochir (Wien) 161(2):371–378. https://doi.org/10.1007/s00701-019-03811-w

    Article  PubMed  Google Scholar 

  22. Roy V, Ross JP, Pépin R et al (2022) (2022) Moyamoya disease susceptibility gene RNF213 regulates endothelial barrier function. Stroke 53(4):1263–1275. https://doi.org/10.1161/STROKEAHA.120.032691

    Article  CAS  PubMed  Google Scholar 

  23. Winkler EA, Bell RD, Zlokovic BV (2011) Central nervous system pericytes in health and disease. Nat Neurosci 14(11):1398–1405. https://doi.org/10.1038/nn.2946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sweeney MD, Ayyadurai S, Zlokovic BV (2016) Pericytes of the neurovascular unit: key functions and signaling pathways. Nat Neurosci 19(6):771–783. https://doi.org/10.1038/nn.4288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Armulik A, Genové G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21(2):193–215. https://doi.org/10.1016/j.devcel.2011.07.001

    Article  CAS  PubMed  Google Scholar 

  26. Aoyagi M, Fukai N, Yamamoto M, Matsushima Y, Yamamoto K (1997) Development of intimal thickening in superficial temporal arteries in patients with moyamoya disease. Clin Neurol Neurosurg 99(Suppl 2):S213–S217. https://doi.org/10.1016/s0303-8467(97)00046-2

    Article  PubMed  Google Scholar 

  27. Winkler EA, Birk H, Burkhardt JK et al (2018) Reductions in brain pericytes are associated with arteriovenous malformation vascular instability. J Neurosurg 129(6):1464–1474. https://doi.org/10.3171/2017.6.JNS17860

    Article  PubMed  PubMed Central  Google Scholar 

  28. Wang K, Zhang HF, He Y et al (2020) Mural cell-specific deletion of cerebral cavernous malformation 3 in the brain induces cerebral cavernous malformations. Arterioscler Thromb Vasc Biol 40(9):2171–2186. https://doi.org/10.1161/ATVBAHA.120.314586

    Article  CAS  PubMed  Google Scholar 

  29. Dai ZF, Li JW, Li Y et al (2022) Role of pericytes in the development of cerebral cavernous malformations. iScience 25(12):105642. https://doi.org/10.1016/j.isci.2022.105642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tsao CC, Baumann J, Huang SF et al (2021) Pericyte hypoxia-inducible factor-1 (HIF-1) drives blood-brain barrier disruption and impacts acute ischemic stroke outcome. Angiogenesis 24(4):823–842. https://doi.org/10.1007/s10456-021-09796-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Machuca-Parra AI, Bigger-Allen AA, Angie V, Sanchez AV et al (2017) Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL. J Exp Med 214(8):2271–2282. https://doi.org/10.1084/jem.20161715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lindahl P, Johansson BR, Levéen P, Betsholtz C (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277(5323):242–245. https://doi.org/10.1126/science.277.5323.242

    Article  CAS  PubMed  Google Scholar 

  33. Luo CM, Liang FY, Ren HX et al (2017) Collateral blood flow in different cerebrovascular hierarchy provides endogenous protection in cerebral ischemia. Brain Pathol 27(6):809–821. https://doi.org/10.1111/bpa.12458

    Article  PubMed  PubMed Central  Google Scholar 

  34. Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, Zlokovic BV (2010) Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68(3):409–427. https://doi.org/10.1016/j.neuron.2010.09.043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nikolakopoulou AM, Zhao Z, Montagne A, Zlokovic BV (2017) Regional early and progressive loss of brain pericytes but not vascular smooth muscle cells in adult mice with disrupted platelet-derived growth factor receptor-β signaling. PLoS One 12(4):e0176225. https://doi.org/10.1371/journal.pone.0176225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Deng ZZ, Zhou L, Wang YG et al (2020) Astrocyte-derived VEGF increases cerebral microvascular permeability under high salt conditions. Aging (Albany NY) 12(12):11781–11793. https://doi.org/10.18632/aging.103348

    Article  CAS  PubMed  Google Scholar 

  37. Kobayashi H, Yamazaki S, Takashima S et al (2013) Ablation of Rnf213 retards progression of diabetes in the Akita mouse. Biochem Biophys Res Commun 432(3):519–525. https://doi.org/10.1016/j.bbrc.2013.02.015

    Article  CAS  PubMed  Google Scholar 

  38. Aoyagi M, Fukai N, Yamamoto M, Nakagawa K, Matsushima Y, Yamamoto K (1996) Early development of intimal thickening in superficial temporal arteries in patients with moyamoya disease. Stroke 27(10):1750–4. https://doi.org/10.1161/01.str.27.10.1750

    Article  CAS  PubMed  Google Scholar 

  39. Savage JC, Carrier M, Tremblay M (2019) Morphology of microglia across contexts of health and disease. Methods Mol Biol 2034:13–26. https://doi.org/10.1007/978-1-4939-9658-2_2

    Article  CAS  PubMed  Google Scholar 

  40. Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468(7323):562–566. https://doi.org/10.1038/nature09513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hellström M, Gerhardt H, Kalén M, Li X, Eriksson U, Wolburg H, Betsholtz C (2001) Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 153(3):543–553. https://doi.org/10.1083/jcb.153.3.543

    Article  PubMed  PubMed Central  Google Scholar 

  42. Miyawaki S, Imai H, Takayanagi S, Mukasa A, Nakatomi H, Saito N (2012) Identification of a genetic variant common to moyamoya disease and intracranial major artery stenosis/occlusion. Stroke 43(12):3371–3374. https://doi.org/10.1161/STROKEAHA.112.663864

    Article  PubMed  Google Scholar 

  43. Okazaki S, Morimoto T, Kamatani Y et al (2019) Moyamoya disease susceptibility variant RNF213 p.R4810K increases the risk of ischemic stroke attributable to large-artery atherosclerosis. Circulation 139(2):295–298. https://doi.org/10.1161/CIRCULATIONAHA.118.038439

    Article  CAS  PubMed  Google Scholar 

  44. Yuta Fukushima Y, Miyawaki S, Inoue et al (2015) Repeated de novo aneurysm formation after anastomotic surgery: potential risk of genetic variant RNF213 c.14576G>A. Surg Neurol Int 6:41. https://doi.org/10.4103/2152-7806.153709

    Article  PubMed  PubMed Central  Google Scholar 

  45. Armulik A, Genové G, Mäe M et al (2010) Pericytes regulate the blood-brain barrier. Nature 468(7323):557–561. https://doi.org/10.1038/nature09522

    Article  CAS  PubMed  Google Scholar 

  46. Yang Y, Rosenberg GA (2011) Rosenberg, Blood-brain barrier breakdown in acute and chronic cerebrovascular disease. Stroke 42(11):3323–8. https://doi.org/10.1161/STROKEAHA.110.608257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Walsh J, Tozer DJ, Sari H et al (2021) Microglial activation and blood-brain barrier permeability in cerebral small vessel disease. Brain 144(5):1361–1371. https://doi.org/10.1093/brain/awab003

    Article  PubMed  PubMed Central  Google Scholar 

  48. Rajeev V, Fann DY, Dinh QN et al (2022) Pathophysiology of blood brain barrier dysfunction during chronic cerebral hypoperfusion in vascular cognitive impairment. Theranostics 12(4):1639–1658. https://doi.org/10.7150/thno.68304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Fujimura M, Shimizu H, Inoue T, Mugikura S, Saito A, Tominaga T (2011) Significance of focal cerebral hyperperfusion as a cause of transient neurologic deterioration after extracranial-intracranial bypass for moyamoya disease: comparative study with non-moyamoya patients using N-isopropyl-p-[(123)I]iodoamphetamine single-photon emission computed tomography. Neurosurgery 68(4):957–64. https://doi.org/10.1227/NEU.0b013e318208f1da. (discussion 964-5)

    Article  PubMed  Google Scholar 

  50. Fujimura M, Niizuma K, Inoue T, Sato K, Endo H, Shimizu H, Tominaga T (2014) Minocycline prevents focal neurological deterioration due to cerebral hyperperfusion after extracranial-intracranial bypass for moyamoya disease. Neurosurgery 74(2):163–70. https://doi.org/10.1227/NEU.0000000000000238. (discussion 170)

    Article  PubMed  Google Scholar 

  51. Kang HS, Kim JH, Phi JH et al (2010) Plasma matrix metalloproteinases, cytokines and angiogenic factors in moyamoya disease. J Neurol Neurosurg Psychiatry 81(6):673–8. https://doi.org/10.1136/jnnp.2009.191817

    Article  PubMed  Google Scholar 

  52. Sonobe S, Fujimura M, Niizuma K et al (2014) Increased vascular MMP-9 in mice lacking RNF213: moyamoya disease susceptibility gene. NeuroReport 25(18):1442–1446. https://doi.org/10.1097/WNR.0000000000000289

    Article  CAS  PubMed  Google Scholar 

  53. Sun ZY, Gao CH, Dandan Gao DD et al (2021) Reduction in pericyte coverage leads to blood-brain barrier dysfunction via endothelial transcytosis following chronic cerebral hypoperfusion. Fluids Barriers CNS 18(1):21. https://doi.org/10.1186/s12987-021-00255-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yoshimoto T, Houkin K, Takahashi A, Abe H (1997) Evaluation of cytokines in cerebrospinal fluid from patients with moyamoya disease. Clin Neurol Neurosurg 99(Suppl 2):S218–S220. https://doi.org/10.1016/s0303-8467(97)00047-4

    Article  PubMed  Google Scholar 

  55. Han WX, Jin F, Zhang HL et al (2020) Association of brain-gut peptides with inflammatory cytokines in moyamoya disease. Mediators Inflamm 2020:5847478. https://doi.org/10.1155/2020/5847478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Han WX, Qiao Y, Zhang HL et al (2021) Circulating sortilin levels are associated with inflammation in patients with moyamoya disease. Metab Brain Dis 36(1):103–109. https://doi.org/10.1007/s11011-020-00616-0

    Article  PubMed  Google Scholar 

  57. Masuda J (1993) Ogata J and Yutani C (1993) Smooth muscle cell proliferation and localization of macrophages and T cells in the occlusive intracranial major arteries in moyamoya disease. Stroke 24(12):1960–1967. https://doi.org/10.1161/01.str.24.12.1960

    Article  CAS  PubMed  Google Scholar 

  58. Török O, Schreiner B, Schaffenrath J et al (2021) Pericytes regulate vascular immune homeostasis in the CNS. Proc Natl Acad Sci U S A 118(10):e2016587118. https://doi.org/10.1073/pnas.2016587118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rustenhoven J, Jansson D, Smyth LC, Dragunow M (2017) Brain pericytes as mediators of neuroinflammation. Trends Pharmacol Sci 38(3):291–304. https://doi.org/10.1016/j.tips.2016.12.001

    Article  CAS  PubMed  Google Scholar 

  60. Starosolski Z, Villamizar CA, Rendon D, Paldino MJ, Milewicz DM, Ghaghada KB, Annapragada AV (2015) Ultra high-resolution in vivo computed tomography imaging of mouse cerebrovasculature using a long circulating blood pool contrast agent. Sci Rep 5:10178. https://doi.org/10.1038/srep10178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Roberts JM, Maniskas ME, Fraser JF, Bix GJ (2018) Internal carotid artery stenosis: a novel surgical model for moyamoya syndrome. PLoS One 13(1):e0191312. https://doi.org/10.1371/journal.pone.0191312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to express the most sincere thanks to Boxing Li from Zhongshan School of Medicine, Sun Yat-sen University, for comments and advice on the article.

Funding

This work was funded by the National Nature Science Foundation of China (82071286, 81671132, 81471180).

Author information

Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China

    Wei Li, Xingyang Niu, Xiaoxin Wu, Jiaoxing Li & Wenli Sheng

  2. Department of Neurology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, China

    Yuanyuan Dai

  3. Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China

    Wenli Sheng

Authors
  1. Wei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xingyang Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuanyuan Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaoxin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiaoxing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wenli Sheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Wei Li, Xingyang Niu, and Yuanyuan Dai. The first draft of the manuscript was written by Wei Li and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Wenli Sheng.

Ethics declarations

Ethics Approval

The procedures involving experimentation on animal subjects are reviewed and approved by the Institutional Animal Care and Use Committee, Sun Yat-Sen University (SYSU-IACUC-2022-001413).

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Wei Li and Xingyang Niu have contributed equally to this work and share first authorship.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 1176 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, W., Niu, X., Dai, Y. et al. Rnf-213 Knockout Induces Pericyte Reduction and Blood-Brain Barrier Impairment in Mouse. Mol Neurobiol 60, 6188–6200 (2023). https://doi.org/10.1007/s12035-023-03480-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-023-03480-y

Keywords

Search

Navigation