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

doi:10.1007/s11515-017-1447-1

Front. Biol.

2017, Vol. 12

Issue (2) : 124-138 https://doi.org/10.1007/s11515-017-1447-1

RESEARCH ARTICLE

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

Gregory W. Kirschen^1,^2,³, Hanxiao Liu³, Tracy Lang^3,⁴, Xuelin Liang³, Shaoyu Ge³, Qiaojie Xiong³(

)

¹. Medical Scientist Training Program (MSTP), Stony Brook University, Stony Brook, NY 11794, USA
². Molecular & Cellular Pharmacology Program, Stony Brook University, Stony Brook, NY 11794, USA
³. Department of Neurobiology & Behavior, Stony Brook University, Stony Brook, NY 11794, USA
⁴. Simons Summer Research Program (SSRP)

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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

Corresponding Author(s): Qiaojie Xiong

Just Accepted Date: 17 February 2017 Online First Date: 20 March 2017 Issue Date: 14 April 2017

Cite this article:

Gregory W. Kirschen,Hanxiao Liu,Tracy Lang, et al. The radial organization of neuronal primary cilia is acutely disrupted by seizure and ischemic brain injury[J]. Front. Biol., 2017, 12(2): 124-138.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-017-1447-1
https://academic.hep.com.cn/fib/EN/Y2017/V12/I2/124

Fig.1 Neuronal primary cilia are radially aligned throughout the cortex.

Fig.2 Neuronal primary cilia alignment in the cortex.

Fig.3 Neuronal primary cilia alignment in dorsal striatum, thalamus, and dentate gyrus.

Fig.4 Distribution of neuronal primary cilia angles and positions in dorsal striatum, thalamus, and dentate gyrus.

Fig.5 Pilocarpine-induced seizure disrupted primary cilia alignment in cortical neurons.

Fig.6 Pilocarpine-induced seizure disrupted primary cilia alignment in hippocampal and striatal neurons.

Fig.7 Internal carotid artery occlusion disrupted primary cilia alignment in cortical neurons.

Fig.8 Internal carotid artery occlusion affected primary cilia alignment in the dentate gyrus but not in striatum or thalamus.

Fig.9 Primary cilia length and number in seizure and ischemia.

1	Albrecht P J, Dahl J P, Stoltzfus O K, Levenson R, Levison S W (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): 46–62 https://doi.org/10.1006/exnr.2001.7834
2	Benes F M, Berretta S (2001). GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology, 25(1): 1–27 https://doi.org/10.1016/S0893-133X(01)00225-1
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): 4242–4246 https://doi.org/10.1073/pnas.0711027105
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–R535 https://doi.org/10.1016/j.cub.2009.05.025
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): 562–571 https://doi.org/10.1002/cne.21510
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): 13127–13132 https://doi.org/10.1073/pnas.0804558105
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): 788–794 https://doi.org/10.1038/nm0796-788
8	Buendia B, Bre M H, 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): 1123–1135 https://doi.org/10.1083/jcb.110.4.1123
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): 694–705 https://doi.org/10.1111/j.1528-1167.2007.01055.x
10	Coyle P (1976). Vascular patterns of the rat hippocampal formation. Exp Neurol, 52(3): 447–458 https://doi.org/10.1016/0014-4886(76)90216-8
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): 143–157 https://doi.org/10.1016/j.jneumeth.2008.04.019
12	DeCaen 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): 315–318 https://doi.org/10.1038/nature12832
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): 1409–1423 https://doi.org/10.1016/j.neuroimage.2006.12.040
14	Dutta R, McDonough 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): 2566–2576 https://doi.org/10.1093/brain/awm206
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): 4306–4314 https://doi.org/10.1523/JNEUROSCI.5295-09.2010
16	Fuchs J L, Schwark H D (2004). Neuronal primary cilia: a review. Cell Biol Int, 28(2): 111–118 https://doi.org/10.1016/j.cellbi.2003.11.008
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: 623–635
18	Goetz S C, Anderson K V (2010). The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet, 11(5): 331–344 https://doi.org/10.1038/nrg2774
19	Han Y G, Alvarez-Buylla A (2010). Role of primary cilia in brain development and cancer. Curr Opin Neurobiol, 20(1): 58–67 https://doi.org/10.1016/j.conb.2009.12.002
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): 277–284 https://doi.org/10.1038/nn2059
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): 909–926 https://doi.org/10.1016/S0306-4522(98)00354-6
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): 567–573 https://doi.org/10.1046/j.1528-1157.2002.29101.x
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): 209–223 https://doi.org/10.1111/neup.12182
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): 79–94 https://doi.org/10.1007/BF00235889
25	Ishikawa H, Marshall W F (2011). Ciliogenesis: building the cell’s antenna. Nat Rev Mol Cell Biol, 12(4): 222–234 https://doi.org/10.1038/nrm3085
26	Khan A A, Mao X O, Banwait S, DerMardirossian C M , Bokoch G M , Jin K, Greenberg D A (2008). Regulation of hypoxic neuronal death signaling by neuroglobin. FASEB J, 22(6): 1737–1747 https://doi.org/10.1096/fj.07-100784
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, S391
28	Lee J E, Gleeson J G (2011). Cilia in the nervous system: linking cilia function and neurodevelopmental disorders. Curr Opin Neurol, 24(2): 98–105 https://doi.org/10.1097/WCO.0b013e3283444d05
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): 1006–1014 https://doi.org/10.1016/S0006-3223(03)00700-5
30	Maguschak K A , Ressler K J (2012). The dynamic role of beta-catenin in synaptic plasticity. Neuropharmacology, 62(1): 78–88 https://doi.org/10.1016/j.neuropharm.2011.08.032
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): 1934–1946 https://doi.org/10.1111/j.1528-1167.2007.01185.x
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): e20580 https://doi.org/10.1371/journal.pone.0020580
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): 519–526 https://doi.org/10.1016/S0002-9378(97)70139-X
34	Pan W X, 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: 147 https://doi.org/10.3389/fnana.2010.00147
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): 81–91 https://doi.org/10.1002/ana.20699
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: 119–127 https://doi.org/10.1016/j.expneurol.2016.05.015
37	Pedersen L B, Rosenbaum J L (2008). Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling. Curr Top Dev Biol, 85: 23–61 https://doi.org/10.1016/S0070-2153(08)00802-8
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): 206–212 https://doi.org/10.1179/1476830515Y.0000000033
39	Quinlan R J, Tobin J L, Beales P L (2008). Modeling ciliopathies: Primary cilia in development and disease. Curr Top Dev Biol, 84: 249–310 https://doi.org/10.1016/S0070-2153(08)00605-4
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: 34370 https://doi.org/10.1038/srep34370
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: 151–158 https://doi.org/10.1016/j.nbd.2014.12.025
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 , Maletić-Savatić M , Encinas J M (2015). Neuronal hyperactivity accelerates depletion of neural stem cells and impairs hippocampal neurogenesis. Cell Stem Cell, 16(5): 488–503 https://doi.org/10.1016/j.stem.2015.04.003
43	Singla V, Reiter J F (2006). The primary cilium as the cell’s antenna: signaling at a sensory organelle. Science, 313(5787): 629–633 https://doi.org/10.1126/science.1124534
44	Spruston N (2008). Pyramidal neurons: dendritic structure and synaptic integration. Nat Rev Neurosci, 9(3): 206–221 https://doi.org/10.1038/nrn2286
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): e74428 https://doi.org/10.1371/journal.pone.0074428
46	Valente E M, Rosti R O, Gibbs E, Gleeson J G (2014). Primary cilia in neurodevelopmental disorders. Nat Rev Neurol, 10(1): 27–36 https://doi.org/10.1038/nrneurol.2013.247
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): 5557–5561 https://doi.org/10.1523/JNEUROSCI.6561-10.2011
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): 444–450 https://doi.org/10.1513/pats.201103-025SD
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): 5865–5869 https://doi.org/10.1073/pnas.92.13.5865
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): 1167–1171 https://doi.org/10.1177/44.10.8813082
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): 1890–1896 https://doi.org/10.1161/01.STR.32.8.1890
52	Yin Y, Zhao X, Fang Y , Huang L (2010). Carotid artery wire injury mouse model with a nonmicrosurgical procedure. Vascular, 18(4): 221–226 https://doi.org/10.2310/6670.2010.00031
53	Yoder B K (2007). Role of primary cilia in the pathogenesis of polycystic kidney disease. J Am Soc Nephrol, 18(5): 1381–1388 https://doi.org/10.1681/ASN.2006111215
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): 3–11 https://doi.org/10.1523/JNEUROSCI.3648-05.2006

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