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Hippocampal enlargement in Bassoon-mutant mice is associated with enhanced neurogenesis, reduced apoptosis, and abnormal BDNF levels

Abstract

Mice mutant for the presynaptic protein Bassoon develop epileptic seizures and an altered pattern of neuronal activity that is accompanied by abnormal enlargement of several brain structures, with the strongest size increase in hippocampus and cortex. Using manganese-enhanced magnetic resonance imaging, an abnormal brain enlargement was found, which is first detected in the hippocampus 1 month after birth and amounts to an almost 40% size increase of this structure after 3 months. Stereological quantification of cell numbers revealed that enlargement of the dentate gyrus and the hippocampus proper is associated with larger numbers of principal neurons and of astrocytes. In search for the underlying mechanisms, an approximately 3-fold higher proportion of proliferation and survival of new-born cells in the dentate gyrus was found to go hand in hand with similarly larger numbers of doublecortin-positive cells and reduced numbers of apoptotic cells in the dentate gyrus and the hippocampus proper. Enlargement of the hippocampus and of other forebrain structures was accompanied by increased levels of brain-derived neurotrophic factor (BDNF). These data show that hippocampal overgrowth in Bassoon-mutant mice arises from a dysregulation of neurogenesis and apoptosis that might be associated with unbalanced BDNF levels.

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References

  1. Almgren M, Persson AS, Fenghua C, Witgen BM, Schalling M, Nyengaard JR, Lavebratt C (2007) Lack of potassium channel induces proliferation and survival causing increased neurogenesis and two-fold hippocampus enlargement. Hippocampus 17:292–304

  2. Almgren M, Schalling M, Lavebratt C (2008) Idiopathic megalencephaly-possible cause and treatment opportunities: from patient to lab. Eur J Paediatr Neurol 12:438–445

  3. Altar CA, Cai N, Bliven T, Juhasz M, Conner JM, Acheson AL, Lindsay RM, Wiegand SJ (1997) Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature 389:856–860

  4. Altar CA, Whitehead RE, Chen R, Wortwein G, Madsen TM (2003) Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biol Psychiatry 54:703–709

  5. Altman J, Bayer SA (1990) Mosaic organization of the hippocampal neuroepithelium and the multiple germinal sources of dentate granule cells. J Comp Neurol 301:325–342

  6. Altrock WD, tom Dieck S, Sokolov M, Meyer AC, Sigler A, Brakebusch C, Fassler R, Richter K, Boeckers TM, Potschka H, Brandt C, Loscher W, Grimberg D, Dresbach T, Hempelmann A, Hassan H, Balschun D, Frey JU, Brandstatter JH, Garner CC, Rosenmund C, Gundelfinger ED (2003) Functional inactivation of a fraction of excitatory synapses in mice deficient for the active zone protein bassoon. Neuron 37:787–800

  7. Amaral DG (1978) A Golgi study of cell types in the hilar region of the hippocampus in the rat. J Comp Neurol 182:851–914

  8. Angenstein F, Niessen HG, Goldschmidt J, Lison H, Altrock WD, Gundelfinger ED, Scheich H (2007) Manganese-enhanced MRI reveals structural and functional changes in the cortex of Bassoon mutant mice. Cereb Cortex 17:28–36

  9. Angenstein F, Hilfert L, Zuschratter W, Altrock WD, Niessen HG, Gundelfinger ED (2008) Morphological and metabolic changes in the cortex of mice lacking the functional presynaptic active zone protein Bassoon: a combined 1H-NMR spectroscopy and histochemical study. Cereb Cortex 18:890–897

  10. Angevine JB Jr (1965) Time of neuron origin in the hippocampal region. An autoradiographic study in the mouse. Exp Neurol Suppl 2:1–70

  11. Baraban SC (2007) Emerging epilepsy models: insights from mice, flies, worms and fish. Curr Opin Neurol 20:164–168

  12. Bayer SA (1980) Development of the hippocampal region in the rat. I. Neurogenesis examined with 3H-thymidine autoradiography. J Comp Neurol 190:87–114

  13. Ben-Ari Y (2008) Neuro-archaeology: pre-symptomatic architecture and signature of neurological disorders. Trends Neurosci 31:626–636

  14. Ben-Ari Y, Holmes GL (2006) Effects of seizures on developmental processes in the immature brain. Lancet Neurol 5:1055–1063

  15. Bibel M, Barde YA (2000) Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system. Genes Dev 14:2919–2937

  16. Binder DK, Croll SD, Gall CM, Scharfman HE (2001) BDNF and epilepsy: too much of a good thing? Trends Neurosci 24:47–53

  17. Blackstad TW (1956) Commissural connections of the hippocampal region in the rat, with special reference to their mode of termination. J Comp Neurol 105:417–537

  18. Blumcke I, Thom M, Wiestler OD (2002) Ammon's horn sclerosis: a maldevelopmental disorder associated with temporal lobe epilepsy. Brain Pathol 12:199–211

  19. Cho SR, Benraiss A, Chmielnicki E, Samdani A, Economides A, Goldman SA (2007) Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease. J Clin Invest 117:2889–2902

  20. Diez M, Schweinhardt P, Petersson S, Wang FH, Lavebratt C, Schalling M, Hokfelt T, Spenger C (2003) MRI and in situ hybridization reveal early disturbances in brain size and gene expression in the megencephalic (mceph/mceph) mouse. Eur J Neurosci 18:3218–3230

  21. Doetsch F (2003) The glial identity of neural stem cells. Nat Neurosci 6:1127–1134

  22. Donahue LR, Cook SA, Johnson KR, Bronson RT, Davisson MT (1996) Megencephaly: a new mouse mutation on chromosome 6 that causes hypertrophy of the brain. Mamm Genome 7:871–876

  23. Dresbach T, Qualmann B, Kessels MM, Garner CC, Gundelfinger ED (2001) The presynaptic cytomatrix of brain synapses. Cell Mol Life Sci 58:94–116

  24. Ehninger D, Kempermann G (2008) Neurogenesis in the adult hippocampus. Cell Tissue Res 331:243–250

  25. Fabel K, Kempermann G (2008) Physical activity and the regulation of neurogenesis in the adult and aging brain. Neuromolecular Med 10:59–66

  26. Ganguly K, Schinder AF, Wong ST, Poo M (2001) GABA itself promotes the developmental switch of neuronal GABAergic responses from excitation to inhibition. Cell 105:521–532

  27. Ghiglieri V, Picconi B, Sgobio C, Bagetta V, Barone I, Paille V, Di Filippo M, Polli F, Gardoni F, Altrock W, Gundelfinger ED, De Sarro G, Bernardi G, Ammassari-Teule M, Di Luca M, Calabresi P (2009) Epilepsy-induced abnormal striatal plasticity in Bassoon mutant mice. Eur J Neurosci 29:1979–1993

  28. Ghiglieri V, Sgobio C, Patassini S, Bagetta V, Fejtova A, Giampa C, Marinucci S, Heyden A, Gundelfinger ED, Fusco FR, Calabresi P, Picconi B (2010) TrkB/BDNF-dependent striatal plasticity and behavior in a genetic model of epilepsy: modulation by valproic acid. Neuropsychopharmacology 35:1531–1540

  29. Gould E (2007) How widespread is adult neurogenesis in mammals? Nat Rev Neurosci 8:481–488

  30. Gozlan H, Ben-Ari Y (2003) Interneurons are the source and the targets of the first synapses formed in the rat developing hippocampal circuit. Cereb Cortex 13:684–692

  31. Gundersen HJ, Bagger P, Bendtsen TF, Evans SM, Korbo L, Marcussen N, Moller A, Nielsen K, Nyengaard JR, Pakkenberg B et al (1988) The new stereological tools: disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis. APMIS 96:857–881

  32. Hallermann S, Fejtova A, Schmidt H, Weyhersmuller A, Silver RA, Gundelfinger ED, Eilers J (2010) Bassoon speeds vesicle reloading at a central excitatory synapse. Neuron 68:710–723

  33. Hong EJ, McCord AE, Greenberg ME (2008) A biological function for the neuronal activity-dependent component of Bdnf transcription in the development of cortical inhibition. Neuron 60:610–624

  34. Houser CR (1991) GABA neurons in seizure disorders: a review of immunocytochemical studies. Neurochem Res 16:295–308

  35. Houser CR (1999) Neuronal loss and synaptic reorganization in temporal lobe epilepsy. Adv Neurol 79:743–761

  36. Jefferys JG (1999) Hippocampal sclerosis and temporal lobe epilepsy: cause or consequence? Brain 122(Pt 6):1007–1008

  37. Jessberger S, Romer B, Babu H, Kempermann G (2005) Seizures induce proliferation and dispersion of doublecortin-positive hippocampal progenitor cells. Exp Neurol 196:342–351

  38. Klausberger T, Marton LF, O'Neill J, Huck JH, Dalezios Y, Fuentealba P, Suen WY, Papp E, Kaneko T, Watanabe M, Csicsvari J, Somogyi P (2005) Complementary roles of cholecystokinin- and parvalbumin-expressing GABAergic neurons in hippocampal network oscillations. J Neurosci 25:9782–9793

  39. Kohara K, Yasuda H, Huang Y, Adachi N, Sohya K, Tsumoto T (2007) A local reduction in cortical GABAergic synapses after a loss of endogenous brain-derived neurotrophic factor, as revealed by single-cell gene knock-out method. J Neurosci 27:7234–7244

  40. Koizumi H, Higginbotham H, Poon T, Tanaka T, Brinkman BC, Gleeson JG (2006) Doublecortin maintains bipolar shape and nuclear translocation during migration in the adult forebrain. Nat Neurosci 9:779–786

  41. Kolbeck R, Bartke I, Eberle W, Barde YA (1999) Brain-derived neurotrophic factor levels in the nervous system of wild-type and neurotrophin gene mutant mice. J Neurochem 72:1930–1938

  42. Lee J, Duan W, Mattson MP (2002) Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem 82:1367–1375

  43. Lledo PM, Alonso M, Grubb MS (2006) Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 7:179–193

  44. Lorente de Nó R (1934) Studies on the structure of the cerebral cortex.II Continuation of the study of the Ammonic system. J Psychol Neurol 46:113–117

  45. Matsumoto T, Rauskolb S, Polack M, Klose J, Kolbeck R, Korte M, Barde YA (2008) Biosynthesis and processing of endogenous BDNF: CNS neurons store and secrete BDNF, not pro-BDNF. Nat Neurosci 11:131–133

  46. Ming GL, Song H (2005) Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28:223–250

  47. Ninkovic J, Mori T, Gotz M (2007) Distinct modes of neuron addition in adult mouse neurogenesis. J Neurosci 27:10906–10911

  48. Palmer TD, Willhoite AR, Gage FH (2000) Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425:479–494

  49. Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS, Lowenstein DH (1997) Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci 17:3727–3738

  50. Pencea V, Bingaman KD, Wiegand SJ, Luskin MB (2001) Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J Neurosci 21:6706–6717

  51. Petersson S, Lavebratt C, Schalling M, Hokfelt T (2000) Expression of cholecystokinin, enkephalin, galanin and neuropeptide Y is markedly changed in the brain of the megencephaly mouse. Neurosci 100:297–317

  52. Rauskolb S, Zagrebelsky M, Dreznjak A, Deogracias R, Matsumoto T, Wiese S, Erne B, Sendtner M, Schaeren-Wiemers N, Korte M, Barde YA (2010) Global deprivation of brain-derived neurotrophic factor in the CNS reveals an area-specific requirement for dendritic growth. J Neurosci 30:1739–1749

  53. Richter K, Langnaese K, Kreutz MR, Olias G, Zhai R, Scheich H, Garner CC, Gundelfinger ED (1999) Presynaptic cytomatrix protein bassoon is localized at both excitatory and inhibitory synapses of rat brain. J Comp Neurol 408:437–448

  54. Rutherford LC, Nelson SB, Turrigiano GG (1998) BDNF has opposite effects on the quantal amplitude of pyramidal neuron and interneuron excitatory synapses. Neuron 21:521–530

  55. Scharfman H, Goodman J, Macleod A, Phani S, Antonelli C, Croll S (2005) Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol 192:348–356

  56. Schmitz C, Hof PR (2005) Design-based stereology in neuroscience. Neurosci 130:813–831

  57. Seri B, Garcia-Verdugo JM, McEwen BS, Alvarez-Buylla A (2001) Astrocytes give rise to new neurons in the adult mammalian hippocampus. J Neurosci 21:7153–7160

  58. Sgobio C, Ghiglieri V, Costa C, Bagetta V, Siliquini S, Barone I, Di Filippo M, Gardoni F, Gundelfinger ED, Di Luca M, Picconi B, Calabresi P (2010) Hippocampal synaptic plasticity, memory, and epilepsy: effects of long-term valproic acid treatment. Biol Psychiatry 67:567–574

  59. Sloviter RS (1999) Status epilepticus-induced neuronal injury and network reorganization. Epilepsia 40(Suppl 1):S34–S39, discussion S40-31

  60. Smalla KH, Matthies H, Langnase K, Shabir S, Bockers TM, Wyneken U, Staak S, Krug M, Beesley PW, Gundelfinger ED (2000) The synaptic glycoprotein neuroplastin is involved in long-term potentiation at hippocampal CA1 synapses. Proc Natl Acad Sci USA 97:4327–4332

  61. Soriano E, Cobas A, Fairen A (1986) Asynchronism in the neurogenesis of GABAergic and non-GABAergic neurons in the mouse hippocampus. Brain Res 395:88–92

  62. Stringer JL (1996) Repeated seizures increase GFAP and vimentin in the hippocampus. Brain Res 717:147–153

  63. tom Dieck S, Sanmarti-Vila L, Langnaese K, Richter K, Kindler S, Soyke A, Wex H, Smalla KH, Kampf U, Franzer JT, Stumm M, Garner CC, Gundelfinger ED (1998) Bassoon, a novel zinc-finger CAG/glutamine-repeat protein selectively localized at the active zone of presynaptic nerve terminals. J Cell Biol 142:499–509

  64. Turrigiano G (2007) Homeostatic signaling: the positive side of negative feedback. Curr Opin Neurobiol 17:318–324

  65. Unsain N, Nunez N, Anastasia A, Masco DH (2008) Status epilepticus induces a TrkB to p75 neurotrophin receptor switch and increases brain-derived neurotrophic factor interaction with p75 neurotrophin receptor: an initial event in neuronal injury induction. Neurosci 154:978–993

  66. Unsain N, Montroull LE, Masco DH (2009) Brain-derived neurotrophic factor facilitates TrkB down-regulation and neuronal injury after status epilepticus in the rat hippocampus. J Neurochem 111:428–440

  67. van Vliet EA, Aronica E, Tolner EA, Lopes da Silva FH, Gorter JA (2004) Progression of temporal lobe epilepsy in the rat is associated with immunocytochemical changes in inhibitory interneurons in specific regions of the hippocampal formation. Exp Neurol 187:367–379

  68. von Bohlen und Halbach O (2007) Immunohistological markers for staging neurogenesis in adult hippocampus. Cell Tissue Res 329:409–420

  69. Wittner L, Eross L, Czirjak S, Halasz P, Freund TF, Magloczky Z (2005) Surviving CA1 pyramidal cells receive intact perisomatic inhibitory input in the human epileptic hippocampus. Brain 128:138–152

  70. Wyneken U, Marengo JJ, Villanueva S, Soto D, Sandoval R, Gundelfinger ED, Orrego F (2003) Epilepsy-induced changes in signaling systems of human and rat postsynaptic densities. Epilepsia 44:243–246

  71. Yokoi T, Tokuhara D, Saito M, Ichiba H, Yamano T (2007) Hippocampal BDNF and TrkB expression in young rats after status epilepticus. Osaka City Med J 53:63–71

  72. Yuan J, Yankner BA (2000) Apoptosis in the nervous system. Nature 407:802–809

  73. Zhai R, Olias G, Chung WJ, Lester RA, tom Dieck S, Langnaese K, Kreutz MR, Kindler S, Gundelfinger ED, Garner CC (2000) Temporal appearance of the presynaptic cytomatrix protein bassoon during synaptogenesis. Mol Cell Neurosci 15:417–428

  74. Zhai RG, Vardinon-Friedman H, Cases-Langhoff C, Becker B, Gundelfinger ED, Ziv NE, Garner CC (2001) Assembling the presynaptic active zone: a characterization of an active one precursor vesicle. Neuron 29:131–143

  75. Zhang W, Yamawaki R, Wen X, Uhl J, Diaz J, Prince DA, Buckmaster PS (2009) Surviving hilar somatostatin interneurons enlarge, sprout axons, and form new synapses with granule cells in a mouse model of temporal lobe epilepsy. J Neurosci 29:14247–14256

  76. Zigova T, Pencea V, Wiegand SJ, Luskin MB (1998) Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb. Mol Cell Neurosci 11:234–245

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Acknowledgements

We wish to thank Kathrin Baldauf, Eike Budinger, Anna Fejtova, Jürgen Goldschmidt, Gisela Grecksch, Thomas Roskoden and Henning Scheich for advice and many helpful discussions. We thank Yves-Alain Barde for support and highly valuable comments on the manuscript. We are grateful to Kathrin Gruss, Karla Krautwald, and Kathrin Pohlmann for expert technical assistance.

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Correspondence to Frank Angenstein.

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This work was supported by the Pakt für Forschung und Innovation of the Leibniz Society, the Deutsche Forschungsgemeinschaft (SFB 779) and the EC contract number 222918 (REPLACES) FP7 - Thematic priority HEALTH.

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Heyden, A., Ionescu, M.S., Romorini, S. et al. Hippocampal enlargement in Bassoon-mutant mice is associated with enhanced neurogenesis, reduced apoptosis, and abnormal BDNF levels. Cell Tissue Res 346, 11 (2011). https://doi.org/10.1007/s00441-011-1233-3

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Keywords

  • Brain-derived neurotrophic factor
  • Epilepsy
  • Hippocampus
  • Presynapse
  • Mouse (Bsn mutant)