Frontiers in Biology

, Volume 12, Issue 2, pp 124–138 | Cite as

The radial organization of neuronal primary cilia is acutely disrupted by seizure and ischemic brain injury

  • Gregory W. Kirschen
  • Hanxiao Liu
  • Tracy Lang
  • Xuelin Liang
  • Shaoyu Ge
  • Qiaojie Xiong
Research Article

Abstract

Background

Neuronal primary cilia are sensory organelles that are critically involved in the proper growth, development, and function of the central nervous system (CNS). Recent work also suggests that they signal in the context of CNS injury, and that abnormal ciliary signaling may be implicated in neurological diseases.

Methods

We quantified the distribution of neuronal primary cilia alignment throughout the normal adult mouse brain by immunohistochemical staining for the primary cilia marker adenylyl cyclase III (ACIII) and measuring the angles of primary cilia with respect to global and local coordinate planes. We then introduced two different models of acute brain insult—temporal lobe seizure and cerebral ischemia, and re-examined neuronal primary cilia distribution, as well as ciliary lengths and the proportion of neurons harboring cilia.

Results

Under basal conditions, cortical cilia align themselves radially with respect to the cortical surface, while cilia in the dentate gyrus align themselves radially with respect to the granule cell layer. Cilia of neurons in the striatum and thalamus, by contrast, exhibit a wide distribution of ciliary arrangements. In both cases of acute brain insult, primary cilia alignment was significantly disrupted in a region-specific manner, with areas affected by the insult preferentially disrupted. Further, the two models promoted differential effects on ciliary lengths, while only the ischemia model decreased the proportion of ciliated cells.

Conclusions

These findings provide evidence for the regional anatomical organization of neuronal primary cilia in the adult brain and suggest that various brain insults may disrupt this organization.

Keywords

cerebral cortex dentate gyrus temporal lobe seizure cerebral ischemia 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Notes

Acknowledgements

This work was supported by 1R21AG046875 and R01NS089770 to S.G., 1F30MH110103 to G.W.K., and departmental internal funding to Q.X., and the Simons Summer Research Program (SSRP) to Tracy Lang.

Supplementary material

11515_2017_1447_MOESM1_ESM.pdf (1.4 mb)
The radial organization of neuronal primary cilia is acutely disrupted by seizure and ischemic brain injury

References

  1. Albrecht P J, Dahl J P, Stoltzfus O K, Levenson R, Levison SW (2002). Ciliary neurotrophic factor activates spinal cord astrocytes, stimulating their production and release of fibroblast growth factor-2, to increase motor neuron survival. Exp Neurol, 173(1): 46–62CrossRefPubMedGoogle Scholar
  2. Benes F M, Berretta S (2001). GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology, 25(1): 1–27CrossRefPubMedGoogle Scholar
  3. Berbari N F, Lewis J S, Bishop G A, Askwith C C, Mykytyn K (2008). Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc Natl Acad Sci USA, 105(11): 4242–4246CrossRefPubMedPubMedCentralGoogle Scholar
  4. Berbari N F, O’Connor A K, Haycraft C J, Yoder B K (2009). The primary cilium as a complex signaling center. Curr Biol, 19(13): R526–R535CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bishop G A, Berbari N F, Lewis J, Mykytyn K (2007). Type III adenylyl cyclase localizes to primary cilia throughout the adult mouse brain. J Comp Neurol, 505(5): 562–571CrossRefPubMedGoogle Scholar
  6. Breunig J J, Sarkisian M R, Arellano J I, Morozov Y M, Ayoub A E, Sojitra S, Wang B, Flavell R A, Rakic P, Town T (2008). Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling. Proc Natl Acad Sci USA, 105(35): 13127–13132CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bruce A J, Boling W, Kindy M S, Peschon J, Kraemer P J, Carpenter M K, Holtsberg F W, Mattson M P (1996). Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat Med, 2(7): 788–794CrossRefPubMedGoogle Scholar
  8. Buendia B, BreMH, Griffiths G, Karsenti E (1990). Cytoskeletal control of centrioles movement during the establishment of polarity in Madin-Darby canine kidney cells. J Cell Biol, 110(4): 1123–1135CrossRefPubMedGoogle Scholar
  9. Busceti C L, Biagioni F, Aronica E, Riozzi B, Storto M, Battaglia G, Giorgi F S, Gradini R, Fornai F, Caricasole A, Nicoletti F, Bruno V (2007). Induction of the Wnt inhibitor, Dickkopf-1, is associated with neurodegeneration related to temporal lobe epilepsy. Epilepsia, 48(4): 694–705CrossRefPubMedGoogle Scholar
  10. Coyle P (1976). Vascular patterns of the rat hippocampal formation. Exp Neurol, 52(3): 447–458CrossRefPubMedGoogle Scholar
  11. Curia G, Longo D, Biagini G, Jones R S, Avoli M (2008). The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods, 172(2): 143–157CrossRefPubMedPubMedCentralGoogle Scholar
  12. De Caen P G, Delling M, Vien T N, Clapham D E (2013). Direct recording and molecular identification of the calcium channel of primary cilia. Nature, 504(7479): 315–318CrossRefGoogle Scholar
  13. Dorr A, Sled J G, Kabani N (2007). Three-dimensional cerebral vasculature of the CBA mouse brain: a magnetic resonance imaging and micro computed tomography study. Neuroimage, 35(4): 1409–1423CrossRefPubMedGoogle Scholar
  14. Dutta R, Mc Donough J, Chang A, Swamy L, Siu A, Kidd G J, Rudick R, Mirnics K, Trapp B D (2007). Activation of the ciliary neurotrophic factor (CNTF) signalling pathway in cortical neurons of multiple sclerosis patients. Brain, 130(10): 2566–2576CrossRefPubMedGoogle Scholar
  15. Einstein E B, Patterson C A, Hon B J, Regan K A, Reddi J, Melnikoff D E, Mateer M J, Schulz S, Johnson B N, Tallent M K (2010). Somatostatin signaling in neuronal cilia is critical for object recognition memory. J Neurosci, 30(12): 4306–4314CrossRefPubMedPubMedCentralGoogle Scholar
  16. Fuchs J L, Schwark H D (2004). Neuronal primary cilia: a review. Cell Biol Int, 28(2): 111–118CrossRefPubMedGoogle Scholar
  17. Garcia J H, Yoshida Y, Chen H, Li Y, Zhang Z G, Lian J, Chen S, Chopp M (1993). Progression from ischemic injury to infarct following middle cerebral artery occlusion in the rat. Am J Pathol, 142: 623–635PubMedPubMedCentralGoogle Scholar
  18. Goetz S C, Anderson K V (2010). The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet, 11(5): 331–344CrossRefPubMedPubMedCentralGoogle Scholar
  19. Han Y G, Alvarez-Buylla A (2010). Role of primary cilia in brain development and cancer. Curr Opin Neurobiol, 20(1): 58–67CrossRefPubMedPubMedCentralGoogle Scholar
  20. Han Y G, Spassky N, Romaguera-Ros M, Garcia-Verdugo J M, Aguilar A, Schneider-Maunoury S, Alvarez-Buylla A (2008). Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat Neurosci, 11(3): 277–284CrossRefPubMedGoogle Scholar
  21. Handel M, Schulz S, Stanarius A, Schreff M, Erdtmann-Vourliotis M, Schmidt H, Wolf G, Hollt V (1999). Selective targeting of somatostatin receptor 3 to neuronal cilia. Neuroscience, 89(3): 909–926CrossRefPubMedGoogle Scholar
  22. Huang L T, Yang S N, Liou C W, Hung P L, Lai M C, Wang C L, Wang T J (2002). Pentylenetetrazol-induced recurrent seizures in rat pups: time course on spatial learning and long-term effects. Epilepsia, 43(6): 567–573CrossRefPubMedGoogle Scholar
  23. Inose Y, Kato Y, Kitagawa K, Uchiyama S, Shibata N (2015). Activated microglia in ischemic stroke penumbra upregulate MCP-1 and CCR2 expression in response to lysophosphatidylcholine derived from adjacent neurons and astrocytes. Neuropathology, 35(3): 209–223CrossRefPubMedGoogle Scholar
  24. Irle E, Markowitsch H J (1982). Connections of the hippocampal formation, mamillary bodies, anterior thalamus and cingulate cortex. A retrograde study using horseradish peroxidase in the cat. Exp Brain Res, 47(1): 79–94PubMedGoogle Scholar
  25. Ishikawa H, Marshall W F (2011). Ciliogenesis: building the cell’s antenna. Nat Rev Mol Cell Biol, 12(4): 222–234CrossRefPubMedGoogle Scholar
  26. Khan A A, Mao X O, Banwait S, Der Mardirossian C M, Bokoch G M, Jin K, Greenberg D A (2008). Regulation of hypoxic neuronal death signaling by neuroglobin. FASEB J, 22(6): 1737–1747CrossRefPubMedPubMedCentralGoogle Scholar
  27. Kumamoto N, Gu Y, Wang J, Janoschka S, Takemaru K, Levine J, Ge S (2012). A role for primary cilia in glutamatergic synaptic integration of adult-born neurons. Nat Neurosci, 15: 399–405, S391CrossRefPubMedPubMedCentralGoogle Scholar
  28. Lee J E, Gleeson J G (2011). Cilia in the nervous system: linking cilia function and neurodevelopmental disorders. Curr Opin Neurol, 24(2): 98–105CrossRefPubMedPubMedCentralGoogle Scholar
  29. Madsen T M, Newton S S, Eaton M E, Russell D S, Duman R S (2003). Chronic electroconvulsive seizure up-regulates beta-catenin expression in rat hippocampus: role in adult neurogenesis. Biol Psychiatry, 54(10): 1006–1014CrossRefPubMedGoogle Scholar
  30. Maguschak K A, Ressler K J (2012). The dynamic role of beta-catenin in synaptic plasticity. Neuropharmacology, 62(1): 78–88CrossRefPubMedGoogle Scholar
  31. Marchi N, Oby E, Batra A, Uva L, De Curtis M, Hernandez N, Van Boxel-Dezaire A, Najm I, Janigro D (2007). In vivo and in vitro effects of pilocarpine: relevance to ictogenesis. Epilepsia, 48(10): 1934–1946CrossRefPubMedPubMedCentralGoogle Scholar
  32. Massinen S, Hokkanen M E, Matsson H, Tammimies K, Tapia-Paez I, Dahlstrom-Heuser V, Kuja-Panula J, Burghoorn J, Jeppsson K E, Swoboda P, Peyrard-Janvid M, Toftgård R, Castrén E, Kere J (2011). Increased expression of the dyslexia candidate gene DCDC2 affects length and signaling of primary cilia in neurons. PLoS One, 6(6): e20580CrossRefPubMedPubMedCentralGoogle Scholar
  33. Ota A, Ikeda T, Ikenoue T, Toshimori K (1997). Sequence of neuronal responses assessed by immunohistochemistry in the newborn rat brain after hypoxia-ischemia. Am J Obstet Gynecol, 177(3): 519–526CrossRefPubMedGoogle Scholar
  34. Pan WX, Mao T, Dudman J T (2010). Inputs to the dorsal striatum of the mouse reflect the parallel circuit architecture of the forebrain. Front Neuroanat, 4: 147CrossRefPubMedPubMedCentralGoogle Scholar
  35. Parent J M, Elliott R C, Pleasure S J, Barbaro N M, Lowenstein D H (2006). Aberrant seizure-induced neurogenesis in experimental temporal lobe epilepsy. Ann Neurol, 59(1): 81–91CrossRefPubMedGoogle Scholar
  36. Parker A K, Le M M, Smith T S, Hoang-Minh L B, Atkinson E W, Ugartemendia G, Semple-Rowland S, Coleman J E, Sarkisian M R (2016). Neonatal seizures induced by pentylenetetrazol or kainic acid disrupt primary cilia growth on developing mouse cortical neurons. Exp Neurol, 282: 119–127CrossRefPubMedGoogle Scholar
  37. Pedersen L B, Rosenbaum J L (2008). Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling. Curr Top Dev Biol, 85: 23–61CrossRefPubMedGoogle Scholar
  38. Pessoa D, Cruz R, Machado B, Tenorio B, Nogueira R (2016). Analysis of electrocorticographic patterns in rats fed standard or hyperlipidic diets in a normal state or during status epilepticus. Nutr Neurosci, 19(5): 206–212CrossRefPubMedGoogle Scholar
  39. Quinlan R J, Tobin J L, Beales P L (2008). Modeling ciliopathies: Primary cilia in development and disease. Curr Top Dev Biol, 84: 249–310CrossRefPubMedGoogle Scholar
  40. Rhee S, Kirschen G W, Gu Y, Ge S (2016). Depletion of primary cilia from mature dentate granule cells impairs hippocampus-dependent contextual memory. Sci Rep, 6: 34370CrossRefPubMedPubMedCentralGoogle Scholar
  41. Rowley S, Liang L P, Fulton R, Shimizu T, Day B, Patel M (2015). Mitochondrial respiration deficits driven by reactive oxygen species in experimental temporal lobe epilepsy. Neurobiol Dis, 75: 151–158CrossRefPubMedPubMedCentralGoogle Scholar
  42. Sierra A, Martin-Suarez S, Valcarcel-Martin R, Pascual-Brazo J, Aelvoet S A, Abiega O, Deudero J J, Brewster A L, Bernales I, Anderson A E, Baekelandt V, Maletic-Savatic M, Encinas J M (2015). Neuronal hyperactivity accelerates depletion of neural stem cells and impairs hippocampal neurogenesis. Cell Stem Cell, 16(5): 488–503CrossRefPubMedPubMedCentralGoogle Scholar
  43. Singla V, Reiter J F (2006). The primary cilium as the cell’s antenna: signaling at a sensory organelle. Science, 313(5787): 629–633CrossRefPubMedGoogle Scholar
  44. Spruston N (2008). Pyramidal neurons: dendritic structure and synaptic integration. Nat Rev Neurosci, 9(3): 206–221CrossRefPubMedGoogle Scholar
  45. Theilhaber J, Rakhade S N, Sudhalter J, Kothari N, Klein P, Pollard J, Jensen F E (2013). Gene expression profiling of a hypoxic seizure model of epilepsy suggests a role for mTOR and Wnt signaling in epileptogenesis. PLoS One, 8(9): e74428CrossRefPubMedPubMedCentralGoogle Scholar
  46. Valente E M, Rosti R O, Gibbs E, Gleeson J G (2014). Primary cilia in neurodevelopmental disorders. Nat Rev Neurol, 10(1): 27–36CrossRefPubMedGoogle Scholar
  47. Wang Z, Phan T, Storm D R (2011). The type 3 adenylyl cyclase is required for novel object learning and extinction of contextual memory: role of cAMP signaling in primary cilia. J Neurosci, 31(15): 5557–5561CrossRefPubMedPubMedCentralGoogle Scholar
  48. Ware S M, Aygun M G, Hildebrandt F (2011). Spectrum of clinical diseases caused by disorders of primary cilia. Proc Am Thorac Soc, 8(5): 444–450CrossRefPubMedPubMedCentralGoogle Scholar
  49. Winter C G, Saotome Y, Levison S W, Hirsh D (1995). A role for ciliary neurotrophic factor as an inducer of reactive gliosis, the glial response to central nervous system injury. Proc Natl Acad Sci USA, 92(13): 5865–5869CrossRefPubMedPubMedCentralGoogle Scholar
  50. Wolf H K, Buslei R, Schmidt-Kastner R, Schmidt-Kastner P K, Pietsch T, Wiestler O D, Blumcke I (1996). NeuN: a useful neuronal marker for diagnostic histopathology. J Histochem Cytochem, 44(10): 1167–1171CrossRefPubMedGoogle Scholar
  51. Yagita Y, Kitagawa K, Ohtsuki T, Takasawa K, Miyata T, Okano H, Hori M, Matsumoto M (2001). Neurogenesis by progenitor cells in the ischemic adult rat hippocampus. Stroke, 32(8): 1890–1896CrossRefPubMedGoogle Scholar
  52. Yin Y, Zhao X, Fang Y, Huang L (2010). Carotid artery wire injury mouse model with a nonmicrosurgical procedure. Vascular, 18(4): 221–226CrossRefPubMedGoogle Scholar
  53. Yoder B K (2007). Role of primary cilia in the pathogenesis of polycystic kidney disease. J Am Soc Nephrol, 18(5): 1381–1388CrossRefPubMedGoogle Scholar
  54. Zhao C, Teng E M, Summers R G Jr, Ming G L, Gage F H (2006). Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci, 26(1): 3–11CrossRefPubMedGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Gregory W. Kirschen
    • 1
    • 2
    • 3
  • Hanxiao Liu
    • 3
  • Tracy Lang
    • 3
    • 4
  • Xuelin Liang
    • 3
  • Shaoyu Ge
    • 3
  • Qiaojie Xiong
    • 3
  1. 1.Medical Scientist Training Program (MSTP)Stony Brook UniversityStony BrookUSA
  2. 2.Molecular & Cellular Pharmacology ProgramStony Brook UniversityStony BrookUSA
  3. 3.Department of Neurobiology & BehaviorStony Brook UniversityStony BrookUSA
  4. 4.Simons Summer Research Program (SSRP)Stony BrookUSA

Personalised recommendations