Abstract
The (pro)renin receptor [(P)RR], also known as ATP6AP2 [ATPase 6 accessory protein 2], is highly expressed in the brain. ATP6AP2 plays a role in early brain development, adult hippocampal neurogenesis and in cognitive functions. Lack of ATP6AP2 has deleterious effects, and mutations of ATP6AP2 in humans are associated with, e.g. X-linked intellectual disability. However, little is known about the effects of over-expression of ATP6AP2 in the adult brain. We hypothesized that mice over-expressing ATP6AP2 in the brain might exhibit altered neuroanatomical features and behavioural responses. To this end, we investigated heterozygous transgenic female mice and confirmed increased levels of ATP6AP2 in the brain. Our data show that over-expression of ATP6AP2 does not affect adult hippocampal neurogenesis, exercise-induced cell proliferation, or dendritic spine densities in the hippocampus. Only a reduced ventricular volume on the gross morphological level was found. However, ATP6AP2 over-expressing mice displayed altered exploratory behaviour with respect to the hole-board and novel object recognition tests. Moreover, primary adult hippocampal neural stem cells over-expressing ATP6AP2 exhibit a faster cell cycle progression and increased cell proliferation. Together, in contrast to the known deleterious effects of ATP6AP2 depletion, a moderate over-expression results in moderate behavioural changes and affects cell proliferation rate in vitro.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alenina N, Xu P, Rentzsch B, Patkin EL, Bader M (2008) Genetically altered animal models for Mas and angiotensin-(1–7). Exp Physiol 93(5):528–537. https://doi.org/10.1113/expphysiol.2007.040345
Baryshnikova LM, von Bohlen und Halbach O, Kaplan S, von Bartheld CS (2006) Two distinct events, section compression and loss of particles (“lost caps”), contribute to z-axis distortion and bias in optical disector counting. Microsc Res Tech 69(9):738–756. https://doi.org/10.1002/jemt.20345
Bild W, Ciobica A (2013) Angiotensin-(1–7) central administration induces anxiolytic-like effects in elevated plus maze and decreased oxidative stress in the amygdala. J Affect Disord 145(2):165–171. https://doi.org/10.1016/j.jad.2012.07.024
Contrepas A, Walker J, Koulakoff A, Franek KJ, Qadri F, Giaume C, Corvol P, Schwartz CE, Nguyen G (2009) A role of the (pro)renin receptor in neuronal cell differentiation. Am J Physiol Regul Integr Comp Physiol 297(2):R250–R257. https://doi.org/10.1152/ajpregu.90832.2008
D’Hooge R, De Deyn PP (2001) Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev 36(1):60–90
De Bundel D, Smolders I, Yang R, Albiston AL, Michotte Y, Chai SY (2009) Angiotensin IV and LVV-haemorphin 7 enhance spatial working memory in rats: effects on hippocampal glucose levels and blood flow. Neurobiol Learn Mem 92(1):19–26. https://doi.org/10.1016/j.nlm.2009.02.004
Demyanenko GP, Tsai AY, Maness PF (1999) Abnormalities in neuronal process extension, hippocampal development, and the ventricular system of L1 knockout mice. J Neurosci 19(12):4907–4920
Denny JB, Polan-Curtain J, Wayner MJ, Armstrong DL (1991) Angiotensin II blocks hippocampal long-term potentiation. Brain Res 567(2):321–324
Dokter M, Busch R, Poser R, Vogt MA, von Bohlen und Halbach V, Gass P, Unsicker K, von Bohlen und Halbach O (2015) Implications of p75NTR for dentate gyrus morphology and hippocampus-related behavior revisited. Brain Struct Funct 220(3):1449–1462. https://doi.org/10.1007/s00429-014-0737-5
Douglass JK, Wcislo WT (2010) An inexpensive and portable microvolumeter for rapid evaluation of biological samples. Biotechniques 49(2):566–572. https://doi.org/10.2144/000113464
Dubos A, Castells-Nobau A, Meziane H, Oortveld MA, Houbaert X, Iacono G, Martin C, Mittelhaeuser C, Lalanne V, Kramer JM, Bhukel A, Quentin C, Slabbert J, Verstreken P, Sigrist SJ, Messaddeq N, Birling MC, Selloum M, Stunnenberg HG, Humeau Y, Schenck A, Herault Y (2015) Conditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration. Hum Mol Genet 24(23):6736–6755. https://doi.org/10.1093/hmg/ddv380
Duchemin S, Belanger E, Wu R, Ferland G, Girouard H (2013) Chronic perfusion of angiotensin II causes cognitive dysfunctions and anxiety in mice. Physiol Behav 109:63–68. https://doi.org/10.1016/j.physbeh.2012.10.005
Fedorov A, Beichel R, Kalpathy-Cramer J, Finet J, Fillion-Robin JC, Pujol S, Bauer C, Jennings D, Fennessy F, Sonka M, Buatti J, Aylward S, Miller JV, Pieper S, Kikinis R (2012) 3D Slicer as an image computing platform for the Quantitative Imaging Network. Magn Reson Imaging 30(9):1323–1341. https://doi.org/10.1016/j.mri.2012.05.001
Goncalves JT, Schafer ST, Gage FH (2016) Adult neurogenesis in the hippocampus: from stem cells to behavior. Cell 167(4):897–914. https://doi.org/10.1016/j.cell.2016.10.021
Guo W, Allan AM, Zong R, Zhang L, Johnson EB, Schaller EG, Murthy AC, Goggin SL, Eisch AJ, Oostra BA, Nelson DL, Jin P, Zhao X (2011) Ablation of Fmrp in adult neural stem cells disrupts hippocampus-dependent learning. Nat Med 17(5):559–565. https://doi.org/10.1038/nm.2336
Gupta HV, Vengoechea J, Sahaya K, Virmani T (2015) A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism. Parkinsonism Relat Disord 21(12):1473–1475. https://doi.org/10.1016/j.parkreldis.2015.10.001
Hedera P, Alvarado D, Beydoun A, Fink JK (2002) Novel mental retardation-epilepsy syndrome linked to Xp21.1-p11.4. Ann Neurol 51(1):45–50
Hellner K, Walther T, Schubert M, Albrecht D (2005) Angiotensin-(1–7) enhances LTP in the hippocampus through the G-protein-coupled receptor Mas. Mol Cell Neurosci 29(3):427–435. https://doi.org/10.1016/j.mcn.2005.03.012
Kempermann G, Kuhn HG, Gage FH (1997) More hippocampal neurons in adult mice living in an enriched environment. Nature 386(6624):493–495. https://doi.org/10.1038/386493a0
Kempermann G, Jessberger S, Steiner B, Kronenberg G (2004) Milestones of neuronal development in the adult hippocampus. Trends Neurosci 27(8):447–452. https://doi.org/10.1016/j.tins.2004.05.013
Klempin F, Beis D, Mosienko V, Kempermann G, Bader M, Alenina N (2013) Serotonin is required for exercise-induced adult hippocampal neurogenesis. J Neurosci 33(19):8270–8275. https://doi.org/10.1523/JNEUROSCI.5855-12.2013
Korvatska O, Strand NS, Berndt JD, Strovas T, Chen DH, Leverenz JB, Kiianitsa K, Mata IF, Karakoc E, Greenup JL, Bonkowski E, Chuang J, Moon RT, Eichler EE, Nickerson DA, Zabetian CP, Kraemer BC, Bird TD, Raskind WH (2013) Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity (XPDS). Hum Mol Genet 22(16):3259–3268. https://doi.org/10.1093/hmg/ddt180
Koschützke L, Bertram J, Hartmann B, Bartsch D, Lotze M, von Bohlen und Halbach O (2015) SrGAP3 knockout mice display enlarged lateral ventricles and specific cilia disturbances of ependymal cells in the third ventricle. Cell Tissue Res 361(2):645–650. https://doi.org/10.1007/s00441-015-2224-6
Krop M, Lu X, Danser AH, Meima ME (2013) The (pro)renin receptor. A decade of research: what have we learned? Pflugers Arch 465(1):87–97. https://doi.org/10.1007/s00424-012-1105-z
Lee JE, Gleeson JG (2011) A systems-biology approach to understanding the ciliopathy disorders. Genome Med 3(9):59. https://doi.org/10.1186/gm275
Ludwig J, Kerscher S, Brandt U, Pfeiffer K, Getlawi F, Apps DK, Schagger H (1998) Identification and characterization of a novel 9.2-kDa membrane sector-associated protein of vacuolar proton-ATPase from chromaffin granules. J Biol Chem 273(18):10939–10947
Marlatt MW, Lucassen PJ, van Praag H (2010) Comparison of neurogenic effects of fluoxetine, duloxetine and running in mice. Brain Res 1341:93–99. https://doi.org/10.1016/j.brainres.2010.03.086
Metscher BD (2009a) MicroCT for comparative morphology: simple staining methods allow high-contrast 3D imaging of diverse non-mineralized animal tissues. BMC Physiol 9:11. https://doi.org/10.1186/1472-6793-9-11
Metscher BD (2009b) MicroCT for developmental biology: a versatile tool for high-contrast 3D imaging at histological resolutions. Dev Dyn 238(3):632–640. https://doi.org/10.1002/dvdy.21857
Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer JD (2002) Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 109(11):1417–1427. https://doi.org/10.1172/JCI14276
Peters J (2017) The (pro)renin receptor and its interaction partners. Pflugers Arch. https://doi.org/10.1007/s00424-017-2005-z (Epub ahead of print)
Poorkaj P, Raskind WH, Leverenz JB, Matsushita M, Zabetian CP, Samii A, Kim S, Gazi N, Nutt JG, Wolff J, Yearout D, Greenup JL, Steinbart EJ, Bird TD (2010) A novel X-linked four-repeat tauopathy with Parkinsonism and spasticity. Mov Disord 25(10):1409–1417. https://doi.org/10.1002/mds.23085
Poser R, Dokter M, von Bohlen und Halbach V, Berger SM, Busch R, Baldus M, Unsicker K, von Bohlen und Halbach O (2015) Impact of a deletion of the full-length and short isoform of p75NTR on cholinergic innervation and the population of postmitotic doublecortin positive cells in the dentate gyrus. Front Neuroanat 9:63. https://doi.org/10.3389/fnana.2015.00063
Powell CM, Schoch S, Monteggia L, Barrot M, Matos MF, Feldmann N, Sudhof TC, Nestler EJ (2004) The presynaptic active zone protein RIM1alpha is critical for normal learning and memory. Neuron 42(1):143–153
Ramkumar N, Stuart D, Calquin M, Quadri S, Wang S, Van Hoek AN, Siragy HM, Ichihara A, Kohan DE (2015) Nephron-specific deletion of the prorenin receptor causes a urine concentration defect. Am J Physiol Renal Physiol 309(1):F48-56. https://doi.org/10.1152/ajprenal.00126.2015
Ramser J, Abidi FE, Burckle CA, Lenski C, Toriello H, Wen G, Lubs HA, Engert S, Stevenson RE, Meindl A, Schwartz CE, Nguyen G (2005) A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor. Hum Mol Genet 14(8):1019–1027. https://doi.org/10.1093/hmg/ddi094
Ray J, Gage FH (2006) Differential properties of adult rat and mouse brain-derived neural stem/progenitor cells. Mol Cell Neurosci 31(3):560–573. https://doi.org/10.1016/j.mcn.2005.11.010
Rosendahl A, Niemann G, Lange S, Ahadzadeh E, Krebs C, Contrepas A, van Goor H, Wiech T, Bader M, Schwake M, Peters J, Stahl R, Nguyen G, Wenzel UO (2014) Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice. Lab Invest 94(8):863–872. https://doi.org/10.1038/labinvest.2014.83
Schäfer ST, Peters J, von Bohlen und Halbach O (2013) The (pro)renin receptor/ATP6ap2 is expressed in the murine hippocampus by adult and newly generated neurons. Restor Neurol Neurosci 31(2):225–231. https://doi.org/10.3233/rnn-120282
Schäfer ST, Han J, Pena M, von Bohlen und Halbach O, Peters J, Gage FH (2015) The Wnt adaptor protein ATP6AP2 regulates multiple stages of adult hippocampal neurogenesis. J Neurosci 35(12):4983–4998. https://doi.org/10.1523/JNEUROSCI.4130-14.2015
Sharma S, Rakoczy S, Brown-Borg H (2010) Assessment of spatial memory in mice. Life Sci 87(17–18):521–536. https://doi.org/10.1016/j.lfs.2010.09.004
Tota S, Goel R, Pachauri SD, Rajasekar N, Najmi AK, Hanif K, Nath C (2013) Effect of angiotensin II on spatial memory, cerebral blood flow, cholinergic neurotransmission, and brain derived neurotrophic factor in rats. Psychopharmacology 226(2):357–369. https://doi.org/10.1007/s00213-012-2913-8
Unger T, Badoer E, Ganten D, Lang RE, Rettig R (1988) Brain angiotensin: pathways and pharmacology. Circulation 77(6 Pt 2):I40–I54
van Praag H, Christie BR, Sejnowski TJ, Gage FH (1999) Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA 96(23):13427–13431
van Thiel BS, Goes Martini A, Te Riet L, Severs D, Uijl E, Garrelds IM, Leijten FPJ, van der Pluijm I, Essers J, Qadri F, Alenina N, Bader M, Paulis L, Rajkovicova R, Domenig O, Poglitsch M, Danser AHJ (2017) Brain renin-angiotensin system. Does it exist? Hypertension 69(6):1136–1144. https://doi.org/10.1161/HYPERTENSIONAHA.116.08922
Vogt MA, Chourbaji S, Brandwein C, Dormann C, Sprengel R, Gass P (2008) Suitability of tamoxifen-induced mutagenesis for behavioral phenotyping. Exp Neurol 211(1):25–33. https://doi.org/10.1016/j.expneurol.2007.12.012
von Bartheld C (2002) Counting particles in tissue sections: choices of methods and importance of calibration to minimize biases. Histol Histopathol 17(2):639–648
von Bohlen und Halbach O (2009) Structure and function of dendritic spines within the hippocampus. Ann Anat 191(6):518–531. https://doi.org/10.1016/j.aanat.2009.08.006
von Bohlen und Halbach O (2010) Dendritic spine abnormalities in mental retardation. Cell Tissue Res 342(3):317–323. https://doi.org/10.1007/s00441-010-1070-9
von Bohlen und Halbach O (2011) Immunohistological markers for proliferative events, gliogenesis, and neurogenesis within the adult hippocampus. Cell Tissue Res 345(1):1–19. https://doi.org/10.1007/s00441-011-1196-4
von Bohlen und Halbach O, Albrecht D (1998a) Angiotensin II inhibits long-term potentiation within the lateral nucleus of the amygdala through AT1 receptors. Peptides 19(6):1031–1036
von Bohlen und Halbach O, Albrecht D (1998b) Opposite effects of angiotensin II and IV in the lateral nucleus of the amygdala. Brain Res Bull 47(4):311–315
von Bohlen und Halbach O, Krause S, Medina D, Sciarretta C, Minichiello L, Unsicker K (2006a) Regional- and age-dependent reduction in trkB receptor expression in the hippocampus is associated with altered spine morphologies. Biol Psychiatry 59(9):793–800. https://doi.org/10.1016/j.biopsych.2005.08.025
von Bohlen und Halbach O, Zacher C, Gass P, Unsicker K (2006b) Age-related alterations in hippocampal spines and deficiencies in spatial memory in mice. J Neurosci Res 83(4):525–531. https://doi.org/10.1002/jnr.20759
Wanka H, Lutze P, Staar D, Peters B, Morch A, Vogel L, Chilukoti RK, Homuth G, Sczodrok J, Baumgen I, Peters J (2017) Pro)renin receptor (ATP6AP2) depletion arrests As4.1 cells in the G0/G1 phase thereby increasing formation of primary cilia. J Cell Mol Med 21(7):1394–1410. https://doi.org/10.1111/jcmm.13069
Wayner MJ, Armstrong DL, Polan-Curtain JL, Denny JB (1993) Role of angiotensin II and AT1 receptors in hippocampal LTP. Pharmacol Biochem Behav 45(2):455–464
Wayner MJ, Armstrong DL, Phelix CF, Wright JW, Harding JW (2001) Angiotensin IV enhances LTP in rat dentate gyrus in vivo. Peptides 22(9):1403–1414
Weller S, Gartner J (2001) Genetic and clinical aspects of X-linked hydrocephalus (L1 disease): mutations in the L1CAM gene. Hum Mutat 18(1):1–12. https://doi.org/10.1002/humu.1144
Wincewicz D, Braszko JJ (2015) Angiotensin II AT1 receptor blockade by telmisartan reduces impairment of spatial maze performance induced by both acute and chronic stress. J Renin Angiotensin Aldosterone Syst 16(3):495–505. https://doi.org/10.1177/1470320314526269
Wright JW, Stubley L, Pederson ES, Kramar EA, Hanesworth JM, Harding JW (1999) Contributions of the brain angiotensin IV-AT4 receptor subtype system to spatial learning. J Neurosci 19(10):3952–3961
Acknowledgements
The study was supported by the “Deutsche Forschungsgemeinschaft” (DFG; Grant Numbers: BO1971/6-1; INST 292/119-1 FUGG; INST 292/120-1, PE366/12-1, FUGG, We1688-17-1 and SFB 1192) and the EU (EFRE; UHGWM21).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Informed consent
The work described has not been published before and is not under consideration for publication elsewhere. The manuscript has been approved by all co-authors and all contributors agreed with a submission of the manuscript to the journal “Brain Structure Function”.
Ethical approval
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Human and animal rights statement
This article does not contain any studies with human participants performed by any of the authors.
Rights and permissions
About this article
Cite this article
Bracke, A., Schäfer, S., von Bohlen und Halbach, V. et al. ATP6AP2 over-expression causes morphological alterations in the hippocampus and in hippocampus-related behaviour. Brain Struct Funct 223, 2287–2302 (2018). https://doi.org/10.1007/s00429-018-1633-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00429-018-1633-1