A mouse model of Bardet-Biedl Syndrome has impaired fear memory, which is rescued by lithium treatment

Autoři: Thomas K. Pak aff001;  Calvin S. Carter aff003;  Qihong Zhang aff003;  Sunny C. Huang aff001;  Charles Searby aff003;  Ying Hsu aff003;  Rebecca J. Taugher aff004;  Tim Vogel aff003;  Christopher C. Cychosz aff006;  Rachel Genova aff001;  Nina N. Moreira aff007;  Hanna Stevens aff002;  John A. Wemmie aff002;  Andrew A. Pieper aff009;  Kai Wang aff015;  Val C. Sheffield aff002
Působiště autorů: Medical Scientist Training Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America aff001;  Neuroscience Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America aff002;  Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America aff003;  Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America aff004;  Department of Veterans Affairs Medical Center, Iowa City, Iowa, United States of America aff005;  Department of Orthopedics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America aff006;  Department of Obstetrics and Gynecology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America aff007;  Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America aff008;  Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio, United States of America aff009;  Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio, United States of America aff010;  Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center; Cleveland, Ohio, United States of America aff011;  Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America aff012;  Weill Cornell Autism Research Program, Weill Cornell Medicine of Cornell University, New York, United States of America aff013;  Department of Neuroscience, Case Western Reserve University, School of Medicine, Cleveland, Ohio, United States of America aff014;  Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa, United States of America aff015
Vyšlo v časopise: A mouse model of Bardet-Biedl Syndrome has impaired fear memory, which is rescued by lithium treatment. PLoS Genet 17(4): e1009484. doi:10.1371/journal.pgen.1009484
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009484


Primary cilia are microtubule-based organelles present on most cells that regulate many physiological processes, ranging from maintaining energy homeostasis to renal function. However, the role of these structures in the regulation of behavior remains unknown. To study the role of cilia in behavior, we employ mouse models of the human ciliopathy, Bardet-Biedl Syndrome (BBS). Here, we demonstrate that BBS mice have significant impairments in context fear conditioning, a form of associative learning. Moreover, we show that postnatal deletion of BBS gene function, as well as congenital deletion, specifically in the forebrain, impairs context fear conditioning. Analyses indicated that these behavioral impairments are not the result of impaired hippocampal long-term potentiation. However, our results indicate that these behavioral impairments are the result of impaired hippocampal neurogenesis. Two-week treatment with lithium chloride partially restores the proliferation of hippocampal neurons which leads to a rescue of context fear conditioning. Overall, our results identify a novel role of cilia genes in hippocampal neurogenesis and long-term context fear conditioning.

Klíčová slova:

Cilia – Fear conditioning – Genetically modified animals – Hippocampal neurogenesis – Hippocampus – Lithium – Mice – Mouse models


1. Bavley CC, Rice RC, Fischer DK, Fakira AK, Byrne M, Kosovsky M, et al. Rescue of Learning and Memory Deficits in the Human Nonsyndromic Intellectual Disability Cereblon Knock-Out Mouse Model by Targeting the AMP-Activated Protein Kinase–mTORC1 Translational Pathway. The Journal of Neuroscience. 2018;38(11):2780–95. doi: 10.1523/JNEUROSCI.0599-17.2018 29459374

2. Maulik PK, Mascarenhas MN, Mathers CD, Dua T, Saxena S. Prevalence of intellectual disability: A meta-analysis of population-based studies. Research in Developmental Disabilities. 2011;32(2):419–36. doi: 10.1016/j.ridd.2010.12.018 21236634

3. von Wilamowitz-Moellendorff A, Hunter RW, García-Rocha M, Kang L, López-Soldado I, Lantier L, et al. Glucose-6-phosphate-mediated activation of liver glycogen synthase plays a key role in hepatic glycogen synthesis. Diabetes. 2013;62(12):4070–82. Epub 2013/08/29. doi: 10.2337/db13-0880 23990365

4. Picker JD, Walsh CA. New innovations: therapeutic opportunities for intellectual disabilities. Annals of neurology. 2013;74(3):382–90. Epub 2013/09/17. doi: 10.1002/ana.24002 24038210

5. Scorza CA, Cavalheiro EA. Animal models of intellectual disability: towards a translational approach. Clinics (Sao Paulo, Brazil). 2011;66 Suppl 1(Suppl 1):55–63. doi: 10.1590/s1807-59322011001300007 21779723

6. Oh EC, Vasanth S, Katsanis N. Metabolic regulation and energy homeostasis through the primary Cilium. Cell metabolism. 2015;21(1):21–31. Epub 12/24. doi: 10.1016/j.cmet.2014.11.019 25543293

7. Park SM, Jang HJ, Lee JH. Roles of Primary Cilia in the Developing Brain. Frontiers in Cellular Neuroscience. 2019;13(218).

8. Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. Journal of medical genetics. 1999;36(6):437–46. Epub 2000/06/30. 10874630

9. Forsythe E, Beales PL. Bardet-Biedl syndrome. European journal of human genetics: EJHG. 2013;21(1):8–13. doi: 10.1038/ejhg.2012.115 22713813

10. Sheffield V, Zhang Q, Heon E, drack AV, Stone AEL, Carmi R. Epstein’s Inborn Errors of Development: The Molecular Basis of Clinical Disorders of Morphogenesis: Oxford University Press; 2016.

11. Nachury MV, Loktev AV, Zhang Q, Westlake CJ, Peranen J, Merdes A, et al. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell. 2007;129(6):1201–13. Epub 2007/06/19. doi: 10.1016/j.cell.2007.03.053 17574030

12. Loktev AV, Zhang Q, Beck JS, Searby CC, Scheetz TE, Bazan JF, et al. A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Dev Cell. 2008;15(6):854–65. Epub 2008/12/17. doi: 10.1016/j.devcel.2008.11.001 19081074

13. Mykytyn K, Nishimura DY, Searby CC, Shastri M, Yen HJ, Beck JS, et al. Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome. Nature genetics. 2002;31(4):435–8. doi: 10.1038/ng935 12118255

14. Zhang Q, Seo S, Bugge K, Stone EM, Sheffield VC. BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes. Human Molecular Genetics. 2012;21(9):1945–53. doi: 10.1093/hmg/dds004 22228099

15. Loktev Alexander V, Jackson Peter K. Neuropeptide Y Family Receptors Traffic via the Bardet-Biedl Syndrome Pathway to Signal in Neuronal Primary Cilia. Cell Reports. 2013;5(5):1316–29. doi: 10.1016/j.celrep.2013.11.011 24316073

16. Berbari NF, Lewis JS, Bishop GA, Askwith CC, Mykytyn K. Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc Natl Acad Sci USA. 2008;105. doi: 10.1073/pnas.0711027105 18334641

17. Domire JS, Green JA, Lee KG, Johnson AD, Askwith CC, Mykytyn K. Dopamine receptor 1 localizes to neuronal cilia in a dynamic process that requires the Bardet-Biedl syndrome proteins. Cellular and molecular life sciences: CMLS. 2011;68(17):2951–60. Epub 2010/12/15. doi: 10.1007/s00018-010-0603-4 21152952

18. Leitch CC, Zaghloul NA. BBS4 Is Necessary for Ciliary Localization of TrkB Receptor and Activation by BDNF. PLOS ONE. 2014;9(5):e98687. doi: 10.1371/journal.pone.0098687 24867303

19. Seo S, Baye LM, Schulz NP, Beck JS, Zhang Q, Slusarski DC, et al. BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly. Proceedings of the National Academy of Sciences. 2010;107(4):1488–93.

20. Zhang Q, Nishimura D, Seo S, Vogel T, Morgan DA, Searby C, et al. Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(51):20678–83. Epub 2011/12/06. doi: 10.1073/pnas.1113220108 22139371

21. Weihbrecht K, Goar WA, Pak T, Garrison JE, DeLuca AP, Stone EM, et al. Keeping an Eye on Bardet-Biedl Syndrome: A Comprehensive Review of the Role of Bardet-Biedl Syndrome Genes in the Eye. Medical research archives. 2017;5(9): doi: 10.18103/mra.v5i9.1526 29457131

22. Davis RE, Swiderski RE, Rahmouni K, Nishimura DY, Mullins RF, Agassandian K, et al. A knockin mouse model of the Bardet-Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(49):19422–7. Epub 2007/11/23. doi: 10.1073/pnas.0708571104 18032602

23. Baker K, Northam GB, Chong WK, Banks T, Beales P, Baldeweg T. Neocortical and hippocampal volume loss in a human ciliopathy: A quantitative MRI study in Bardet–Biedl syndrome. American Journal of Medical Genetics Part A. 2011;155(1):1–8.

24. Crawley JN. What’s Wrong With My Mouse?: Behavioral Phenotyping of Transgenic and Knockout Mice: John Wiley & Sons, Inc.; 2006. Available from: https://onlinelibrary.wiley.com/doi/book/10.1002/0470119055.

25. Murru L, Vezzoli E, Longatti A, Ponzoni L, Falqui A, Folci A, et al. Pharmacological Modulation of AMPAR Rescues Intellectual Disability-Like Phenotype in Tm4sf2-/y Mice. Cerebral cortex (New York, NY: 1991). 2017;27(11):5369–84. Epub 2017/10/03. doi: 10.1093/cercor/bhx221 28968657

26. Rajadhyaksha AM, Ra S, Kishinevsky S, Lee AS, Romanienko P, DuBoff M, et al. Behavioral characterization of cereblon forebrain-specific conditional null mice: A model for human non-syndromic intellectual disability. Behavioural brain research. 2012;226(2):428–34. doi: 10.1016/j.bbr.2011.09.039 21995942

27. Matzel LD, Han YR, Grossman H, Karnik MS, Patel D, Scott N, et al. Individual Differences in the Expression of a “General” Learning Ability in Mice. The Journal of Neuroscience. 2003;23(16):6423–33. doi: 10.1523/JNEUROSCI.23-16-06423.2003 12878682

28. Phillips RG, LeDoux JE. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behavioral neuroscience. 1992;106(2):274–85. Epub 1992/04/01. doi: 10.1037//0735-7044.106.2.274 1590953

29. Joshua JP, Christopher CK, Linnaea EO, Joseph LE. Molecular Mechanisms of Fear Learning and Memory. Cell. 2011;147(3):509–24. doi: 10.1016/j.cell.2011.10.009 22036561

30. Abel T, Nguyen PV, Barad M, Deuel TA, Kandel ER, Bourtchouladze R. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell. 1997;88(5):615–26. Epub 1997/03/07. doi: 10.1016/s0092-8674(00)81904-2 9054501

31. Schafe GE, Atkins CM, Swank MW, Bauer EP, Sweatt JD, LeDoux JE. Activation of ERK/MAP Kinase in the Amygdala Is Required for Memory Consolidation of Pavlovian Fear Conditioning. The Journal of Neuroscience. 2000;20(21):8177–87. doi: 10.1523/JNEUROSCI.20-21-08177.2000 11050141

32. Kelley JB, Balda MA, Anderson KL, Itzhak Y. Impairments in fear conditioning in mice lacking the nNOS gene. Learning & memory (Cold Spring Harbor, NY). 2009;16(6):371–8. doi: 10.1101/lm.1329209 19470653

33. Curzon P, Rustay N, Browman K. Methods of Behavior Analysis in Neuroscience. Boca Raton (FL): CRC Press/Taylor & Francis; 2009. Available from: https://www.ncbi.nlm.nih.gov/books/NBK5223/.

34. Eichers ER, Abd-El-Barr MM, Paylor R, Lewis RA, Bi W, Lin X, et al. Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expressivity. Hum Genet. 2006;120(2):211–26. doi: 10.1007/s00439-006-0197-y 16794820

35. Haq N, Schmidt-Hieber C, Sialana FJ, Ciani L, Heller JP, Stewart M, et al. Loss of Bardet-Biedl syndrome proteins causes synaptic aberrations in principal neurons. PLOS Biology. 2019;17(9):e3000414. doi: 10.1371/journal.pbio.3000414 31479441

36. Hsu Y, Garrison JE, Kim G, Schmitz AR, Searby CC, Zhang Q, et al. BBSome function is required for both the morphogenesis and maintenance of the photoreceptor outer segment. PLoS genetics. 2017;13(10):e1007057. doi: 10.1371/journal.pgen.1007057 29049287

37. Li X, Du ZJ, Chen MQ, Chen JJ, Liang ZM, Ding XT, et al. The effects of tamoxifen on mouse behavior. Genes Brain Behav. 2020;19(4):e12620. Epub 2019/10/28. doi: 10.1111/gbb.12620 31652391

38. Gorski JA, Talley T, Qiu M, Puelles L, Rubenstein JLR, Jones KR. Cortical Excitatory Neurons and Glia, But Not GABAergic Neurons, Are Produced in the Emx1-Expressing Lineage. The Journal of Neuroscience. 2002;22(15):6309–14. doi: 20026564 12151506

39. Cooke SF, Bliss TVP. Plasticity in the human central nervous system. Brain: a journal of neurology. 2006;129(7):1659–73. doi: 10.1093/brain/awl082 16672292

40. Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell. 1994;79(1):59–68. doi: 10.1016/0092-8674(94)90400-6 7923378

41. Xie C-W, Sayah D, Chen Q-S, Wei W-Z, Smith D, Liu X. Deficient long-term memory and long-lasting long-term potentiation in mice with a targeted deletion of neurotrophin-4 gene. Proceedings of the National Academy of Sciences. 2000;97(14):8116–21. doi: 10.1073/pnas.140204597 10869436

42. Baker K, Northam GB, Chong WK, Banks T, Beales P, Baldeweg T. Neocortical and hippocampal volume loss in a human ciliopathy: A quantitative MRI study in Bardet-Biedl syndrome. American journal of medical genetics Part A. 2011;155a(1):1–8. Epub 2011/01/05. doi: 10.1002/ajmg.a.33773 21204204

43. Breunig JJ, Sarkisian MR, Arellano JI, Morozov YM, Ayoub AE, Sojitra S, et al. Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(35):13127–32. Epub 2008/08/30. doi: 10.1073/pnas.0804558105 18728187

44. Amador-Arjona A, Elliott J, Miller A, Ginbey A, Pazour GJ, Enikolopov G, et al. Primary Cilia Regulate Proliferation of Amplifying Progenitors in Adult Hippocampus: Implications for Learning and Memory. The Journal of Neuroscience. 2011;31(27):9933–44. doi: 10.1523/JNEUROSCI.1062-11.2011 21734285

45. Brown JP, Couillard-Després S, Cooper-Kuhn CM, Winkler J, Aigner L, Kuhn HG. Transient expression of doublecortin during adult neurogenesis. The Journal of comparative neurology. 2003;467(1):1–10. Epub 2003/10/24. doi: 10.1002/cne.10874 14574675

46. Fiorentini A, Rosi MC, Grossi C, Luccarini I, Casamenti F. Lithium Improves Hippocampal Neurogenesis, Neuropathology and Cognitive Functions in APP Mutant Mice. PLOS ONE. 2010;5(12):e14382. doi: 10.1371/journal.pone.0014382 21187954

47. Carter CS, Vogel TW, Zhang Q, Seo S, Swiderski RE, Moninger TO, et al. Abnormal development of NG2+PDGFR-α+ neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse model. Nature Medicine. 2012;18:1797. doi: 10.1038/nm.2996 23160237

48. Bianchi P, Ciani E, Contestabile A, Guidi S, Bartesaghi R. Lithium Restores Neurogenesis in the Subventricular Zone of the Ts65Dn Mouse, a Model for Down Syndrome. Brain Pathology. 2010;20(1):106–18. doi: 10.1111/j.1750-3639.2008.00246.x 19298631

49. Berbari NF, Malarkey EB, Yazdi SM, McNair AD, Kippe JM, Croyle MJ, et al. Hippocampal and cortical primary cilia are required for aversive memory in mice. PLoS One. 2014;9(9):e106576. Epub 2014/09/04. doi: 10.1371/journal.pone.0106576 25184295

50. Williams CL, Uytingco CR, Green WW, McIntyre JC, Ukhanov K, Zimmerman AD, et al. Gene Therapeutic Reversal of Peripheral Olfactory Impairment in Bardet-Biedl Syndrome. Molecular therapy: the journal of the American Society of Gene Therapy. 2017;25(4):904–16. Epub 02/22. doi: 10.1016/j.ymthe.2017.02.006 28237838

51. Singh M, Garrison JE, Wang K, Sheffield VC. Absence of BBSome function leads to astrocyte reactivity in the brain. Molecular brain. 2019;12(1):48–. doi: 10.1186/s13041-019-0466-z 31072410

52. Fragkouli A, Hearn C, Errington M, Cooke S, Grigoriou M, Bliss T, et al. Loss of forebrain cholinergic neurons and impairment in spatial learning and memory in LHX7-deficient mice. The European journal of neuroscience. 2005;21(11):2923–38. Epub 2005/06/28. doi: 10.1111/j.1460-9568.2005.04141.x 15978004

53. Saxe MD, Battaglia F, Wang J-W, Malleret G, David DJ, Monckton JE, et al. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proceedings of the National Academy of Sciences. 2006;103(46):17501–6. doi: 10.1073/pnas.0607207103 17088541

54. Denny CA, Burghardt NS, Schachter DM, Hen R, Drew MR. 4- to 6-week-old adult-born hippocampal neurons influence novelty-evoked exploration and contextual fear conditioning. Hippocampus. 2012;22(5):1188–201. Epub 2011/07/09. doi: 10.1002/hipo.20964 21739523

55. Imayoshi I, Sakamoto M, Ohtsuka T, Takao K, Miyakawa T, Yamaguchi M, et al. Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nature neuroscience. 2008;11(10):1153–61. Epub 2008/09/02. doi: 10.1038/nn.2185 18758458

56. Deng W, Saxe MD, Gallina IS, Gage FH. Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2009;29(43):13532–42. Epub 2009/10/30.

57. Winocur G, Wojtowicz JM, Sekeres M, Snyder JS, Wang S. Inhibition of neurogenesis interferes with hippocampus-dependent memory function. Hippocampus. 2006;16(3):296–304. Epub 2006/01/18. doi: 10.1002/hipo.20163 16411241

58. Ye F, Nager AR, Nachury MV. BBSome trains remove activated GPCRs from cilia by enabling passage through the transition zone. The Journal of Cell Biology. 2018. doi: 10.1083/jcb.201709041 29483145

59. Nozaki S, Katoh Y, Kobayashi T, Nakayama K. BBS1 is involved in retrograde trafficking of ciliary GPCRs in the context of the BBSome complex. PLoS ONE. 2018;13(3):e0195005. doi: 10.1371/journal.pone.0195005 29590217

60. Bishop GA, Berbari NF, Lewis J, Mykytyn K. Type III adenylyl cyclase localizes to primary cilia throughout the adult mouse brain. The Journal of comparative neurology. 2007;505(5):562–71. Epub 2007/10/11. doi: 10.1002/cne.21510 17924533

61. Lai K, Kaspar BK, Gage FH, Schaffer DV. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nature neuroscience. 2003;6(1):21–7. Epub 2002/12/07. doi: 10.1038/nn983 12469128

62. Han YG, Spassky N, Romaguera-Ros M, Garcia-Verdugo JM, Aguilar A, Schneider-Maunoury S, et al. Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nature neuroscience. 2008;11(3):277–84. Epub 2008/02/26. doi: 10.1038/nn2059 18297065

63. Li Y, Luikart BW, Birnbaum S, Chen J, Kwon CH, Kernie SG, et al. TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron. 2008;59(3):399–412. Epub 2008/08/15. doi: 10.1016/j.neuron.2008.06.023 18701066

64. Islam O, Loo TX, Heese K. Brain-derived neurotrophic factor (BDNF) has proliferative effects on neural stem cells through the truncated TRK-B receptor, MAP kinase, AKT, and STAT-3 signaling pathways. Current neurovascular research. 2009;6(1):42–53. Epub 2009/04/10. doi: 10.2174/156720209787466028 19355925

65. King MK, Jope RS. Lithium treatment alleviates impaired cognition in a mouse model of fragile X syndrome. Genes, Brain and Behavior. 2013;12(7):723–31.

66. Chen G, Rajkowska G, Du F, Seraji-Bozorgzad N, Manji HK. Enhancement of hippocampal neurogenesis by lithium. Journal of neurochemistry. 2000;75(4):1729–34. Epub 2000/09/15. doi: 10.1046/j.1471-4159.2000.0751729.x 10987856

67. Chen G, Rajkowska G, Du F, Seraji-Bozorgzad N, Manji HK. Enhancement of Hippocampal Neurogenesis by Lithium. Journal of neurochemistry. 2000;75(4):1729–34. doi: 10.1046/j.1471-4159.2000.0751729.x 10987856

68. Kessing LV, Gerds TA, Knudsen NN, Jørgensen LF, Kristiansen SM, Voutchkova D, et al. Association of Lithium in Drinking Water With the Incidence of Dementia. JAMA Psychiatry. 2017;74(10):1005–10. doi: 10.1001/jamapsychiatry.2017.2362 28832877

69. Yuan J, Song J, Zhu D, Sun E, Xia L, Zhang X, et al. Lithium Treatment Is Safe in Children With Intellectual Disability. Frontiers in molecular neuroscience. 2018;11:425–. doi: 10.3389/fnmol.2018.00425 30524233

70. Shim SS, Hammonds MD, Mervis RF. Four weeks lithium treatment alters neuronal dendrites in the rat hippocampus. International Journal of Neuropsychopharmacology. 2013;16(6):1373–82. doi: 10.1017/S1461145712001423 23331381

71. Castro AA, Ghisoni K, Latini A, Quevedo J, Tasca CI, Prediger RD. Lithium and valproate prevent olfactory discrimination and short-term memory impairments in the intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rat model of Parkinson’s disease. Behavioural brain research. 2012;229(1):208–15. Epub 2012/01/24. doi: 10.1016/j.bbr.2012.01.016 22266923

72. Guidi S, Bianchi P, Stagni F, Giacomini A, Emili M, Trazzi S, et al. Lithium Restores Age-related Olfactory Impairment in the Ts65Dn Mouse Model of Down Syndrome. CNS & neurological disorders drug targets. 2017;16(7):812–9. Epub 2016/08/05. doi: 10.2174/1871527315666160801143108 27488422

73. Miyoshi K, Kasahara K, Miyazaki I, Asanuma M. Lithium treatment elongates primary cilia in the mouse brain and in cultured cells. Biochem Biophys Res Commun. 2009;388(4):757–62. Epub 2009/08/26. doi: 10.1016/j.bbrc.2009.08.099 19703416

74. Berbari NF, Lewis JS, Bishop GA, Askwith CC, Mykytyn K. Bardet–Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(11):4242–6. doi: 10.1073/pnas.0711027105 18334641

75. Irigoín F, Badano JL. Keeping the balance between proliferation and differentiation: the primary cilium. Current genomics. 2011;12(4):285–97. doi: 10.2174/138920211795860134 22131874

76. Bowie E, Goetz SC. TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons. eLife. 2020;9:e51166. doi: 10.7554/eLife.51166 31934864

77. Zhang Q, Nishimura D, Vogel T, Shao J, Swiderski R, Yin T, et al. BBS7 is required for BBSome formation and its absence in mice results in Bardet-Biedl syndrome phenotypes and selective abnormalities in membrane protein trafficking. Journal of cell science. 2013;126(11):2372–80. doi: 10.1242/jcs.111740 23572516

78. El-Ghundi M, Fletcher PJ, Drago J, Sibley DR, O’Dowd BF, George SR. Spatial learning deficit in dopamine D(1) receptor knockout mice. European journal of pharmacology. 1999;383(2):95–106. Epub 1999/12/11. doi: 10.1016/s0014-2999(99)00573-7 10585522

79. Sarinana J, Kitamura T, Kunzler P, Sultzman L, Tonegawa S. Differential roles of the dopamine 1-class receptors, D1R and D5R, in hippocampal dependent memory. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(22):8245–50. Epub 2014/05/21. doi: 10.1073/pnas.1407395111 24843151

80. Einstein EB, Patterson CA, Hon BJ, Regan KA, Reddi J, Melnikoff DE, et al. Somatostatin signaling in neuronal cilia is critical for object recognition memory. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2010;30(12):4306–14. Epub 2010/03/26.

81. Adamantidis A, Thomas E, Foidart A, Tyhon A, Coumans B, Minet A, et al. Disrupting the melanin-concentrating hormone receptor 1 in mice leads to cognitive deficits and alterations of NMDA receptor function. The European journal of neuroscience. 2005;21(10):2837–44. Epub 2005/06/02. doi: 10.1111/j.1460-9568.2005.04100.x 15926931

82. Guadiana SM, Semple-Rowland S, Daroszewski D, Madorsky I, Breunig JJ, Mykytyn K, et al. Arborization of Dendrites by Developing Neocortical Neurons Is Dependent on Primary Cilia and Type 3 Adenylyl Cyclase. The Journal of Neuroscience. 2013;33(6):2626–38. doi: 10.1523/JNEUROSCI.2906-12.2013 23392690

83. Guo J, Otis JM, Higginbotham H, Monckton C, Cheng J, Asokan A, et al. Primary Cilia Signaling Shapes the Development of Interneuronal Connectivity. Developmental Cell. 2017;42(3):286–300.e4. doi: 10.1016/j.devcel.2017.07.010 28787594

84. Guo W, Allan AM, Zong R, Zhang L, Johnson EB, Schaller EG, et al. Ablation of Fmrp in adult neural stem cells disrupts hippocampus-dependent learning. Nature Medicine. 2011;17(5):559–65. doi: 10.1038/nm.2336 21516088

85. Hersh JH, Saul RA. Health Supervision for Children With Fragile X Syndrome. Pediatrics. 2011;127(5):994–1006. doi: 10.1542/peds.2010-3500 21518720

86. Lee B, Panda S, Lee HY. Primary Ciliary Deficits in the Dentate Gyrus of Fragile X Syndrome. Stem Cell Reports. 2020;15(2):454–66.

87. Lee JW, Lee EJ, Hong SH, Chung WH, Lee HT, Lee TW, et al. Circling mouse: possible animal model for deafness. Comparative medicine. 2001;51(6):550–4. Epub 2002/04/02. 11924819

88. Soken H, Robinson BK, Goodman SS, Abbas PJ, Hansen MR, Kopelovich JC. Mouse cochleostomy: a minimally invasive dorsal approach for modeling cochlear implantation. The Laryngoscope. 2013;123(12):E109–15. Epub 2013/05/16. doi: 10.1002/lary.24174 23674233

89. Mroczka DL, Hoff KM, Goodrich CA, Baker PC. Effect of lithium on reproduction and postnatal growth of mice. Biology of the neonate. 1983;43(5–6):287–96. Epub 1983/01/01. doi: 10.1159/000241657 6871297

90. Yin TC, Britt JK, De Jesus-Cortes H, Lu Y, Genova RM, Khan MZ, et al. P7C3 neuroprotective chemicals block axonal degeneration and preserve function after traumatic brain injury. Cell reports. 2014;8(6):1731–40. Epub 2014/09/16. doi: 10.1016/j.celrep.2014.08.030 25220467

91. Ruxton GD. The unequal variance t-test is an underused alternative to Student’s t-test and the Mann–Whitney U test. Behavioral Ecology. 2006;17(4):688–90.

92. Delacre M, Lakens D, Leys C. Why Psychologists Should by Default Use Welch’s t-test Instead of Student’s t-test. International Review of Social Psychology. 2017;30(1):92–101.

93. Zimmerman DW. A note on preliminary tests of equality of variances. The British journal of mathematical and statistical psychology. 2004;57(Pt 1):173–81. Epub 2004/06/03. doi: 10.1348/000711004849222 15171807

Článek vyšel v časopise

PLOS Genetics

2021 Číslo 4
Nejčtenější tento týden
Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Jak na primární i sekundární osteoporózu − prakticky a v kostce
nový kurz
Autoři: MUDr. Jan Rosa

Léčba roztroušené sklerózy

Důležitost adherence při depresivním onemocnění
Autoři: MUDr. Eliška Bartečková, Ph.D.

Koncepce osteologické péče pro gynekology a praktické lékaře
Autoři: MUDr. František Šenk

Sekvenční léčba schizofrenie
Autoři: MUDr. Jana Hořínková, Ph.D.

Všechny kurzy
Kurzy Podcasty Doporučená témata Časopisy
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se