Skip to main content

Advertisement

SpringerLink
Log in

Antibodies Directed to Neisseria gonorrhoeae Impair Nerve Growth Factor-Dependent Neurite Outgrowth in Rat PC12 Cells

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

In children born from mothers with prenatal infections with the Gram-negative bacterium Neisseria gonorrhoeae, schizophrenia risk is increased in later life. Since cortical neuropil formation is frequently impaired during this disease, actions of a rabbit polyclonal antiserum directed to N. gonorrhoeae on neurite outgrowth in nerve growth factor-stimulated PC12 cells were investigated here. It turned out that 10 μg/ml of the antiserum leads indeed to a significant reduction in neurite outgrowth, whereas an antiserum directed to Neisseria meningitidis had no such effect. Furthermore, reduction in neurite outgrowth could be reversed by the neuroleptic drugs haloperidol, clozapine, risperidone, and olanzapine. On the molecular level, the observed effects seem to include the known neuritogenic transcription factors FoxO3a and Stat3, since reduced neurite outgrowth caused by the antiserum was accompanied by a reduced phosphorylation of both factors. In contrast, restitution of neurite outgrowth by neuroleptic drugs revealed no correlation to the phosphorylation state of these factors. The present report gives a first hint that bacterial infections could indeed lead to impaired neuropil formation in vitro; however, the in vivo relevance of this finding for schizophrenia pathogenesis remains to be clarified in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Babulas V, Factor-Litvak P, Goetz R, Schaefer CA, Brown AS (2006) Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia. Am J Psychiatry 163:927–929

    Article  PubMed  Google Scholar 

  • Bashina VM, Kozlova IA, Kliushnik TP, Simashkova NV, Danilovskaia EV, Gorbachevskaia NL, Turkova IL, Iakupova LP, Grachev VV (1997) An elevation in the level of auto antibodies to nerve-growth factor in the blood serum of schizophrenic children. Zh Nevrol Psikhiatr Im S S Korsakova 97:47–51

    CAS  PubMed  Google Scholar 

  • Benes FM, Davidson J, Bird ED (1986) Quantitative cytoarchitectural studies of the cerebral cortex of schizophrenics. Arch Gen Psychiatry 43:31–35

    Article  CAS  PubMed  Google Scholar 

  • Benes FM, McSparren J, Bird ED, SanGiovanni JP, Vincent SL (1991) Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients. Arch Gen Psychiatry 48:996–1001

    Article  CAS  PubMed  Google Scholar 

  • Black JE, Kodish IM, Grossman AW, Klintsova AY, Orlovskaya D, Vostrikov V, Uranova N, Greenough WT (2004) Pathology of layer V pyramidal neurons in the prefrontal cortex of patients with schizophrenia. Am J Psychiatry 161:742–744

    Article  PubMed  Google Scholar 

  • Broadbelt K, Byne W, Jones LB (2002) Evidence for a decrease in basilar dendrites of pyramidal cells in schizophrenic medial prefrontal cortex. Schizophr Res 58:75–81

    Article  PubMed  Google Scholar 

  • Chen MC, Lin H, Hsu FN, Huang PH, Lee GS, Wang PS (2010) Involvement of cAMP in nerve growth factor-triggered p35/Cdk5 activation and differentiation in PC12-cells. Am J Physiol Cell Physiol 299:C516–C527

    Article  CAS  PubMed  Google Scholar 

  • Dale RC, Brilot F (2012) Autoimmune basal ganglia disorders. J Child Neurol 27:1470–1481

    Article  PubMed  Google Scholar 

  • Darby JK, Pasta DJ, Dabiri L, Clark L, Mosbacher D (1995) Haloperidol dose and blood level variability: toxicity and interindividual and intraindividual variability in the nonresponder patient in the clinical practice setting. J Clin Psychopharmacol 15:334–340

    Article  CAS  PubMed  Google Scholar 

  • Edwards JL, Butler EK (2011) The pathobiology of Neisseria gonorrhoeae lower female genital tract infection. Front Microbiol 2(102):1–12

    Google Scholar 

  • Greene LA (1978) Nerve growth factor prevents the death and stimulates the neuronal differentiation of clonal PC12 pheochromocytoma cells in serum-free medium. J Cell Biol 78:747–755

    Article  CAS  PubMed  Google Scholar 

  • Gur RE, Mozley PD, Shtasel DL, Cannon TD, Gallacher F, Turetsky B, Grossman R, Gur RC (1994) Clinical subtypes of schizophrenia: differences in brain and CSF volume. Am J Psychiatry 151:343–350

    CAS  PubMed  Google Scholar 

  • Harrison PJ (1999) The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 122:593–624

    Article  PubMed  Google Scholar 

  • Henkel AW, Bieger SC (1994) Quantification of proteins dissolved in an electrophoresis sample buffer. Anal Biochem 223:329–331

    Article  CAS  PubMed  Google Scholar 

  • Hoffman TA, Damus AJ, Sands L (1979) Evaluation of a gonococcal serologic test. Am J Clin Pathol 71:184–189

    CAS  PubMed  Google Scholar 

  • Ishima T, Iyo M, Hashimoto K (2012) Neurite outgrowth mediated by the heat shock protein Hsp90α: a novel target for the antipsychotic drug aripiprazole. Transl Psychiatry 2(e170):1–12

    Google Scholar 

  • Jeon CY, Kim HJ, Morii H, Mori N, Settleman J, Lee JY, Kim J, Kim SC, Park JB (2010a) Neurite outgrowth from PC12-cells by basic fibroblast growth factor (bFGF) is mediated by RhoA inactivation through p190RhoGAP and ARAP3. J Cell Physiol 224:786–794

    Article  CAS  PubMed  Google Scholar 

  • Jeon CY, Jin JK, Koh YH, Chun W, Choi IG, Kown HJ, Kim YS, Park JB (2010b) Neurites from PC12 cells are connected to each other by synapse-like structures. Synapse 64:765–772

    CAS  PubMed  Google Scholar 

  • Kalus P, Muller TJ, Zuschratter W, Senitz D (2000) The dendritic architecture of prefrontal pyramidal neurons in schizophrenic patients. Neuroreport 11:3621–3625

    Article  CAS  PubMed  Google Scholar 

  • Kalus P, Bondzio J, Federspiel A, Muller TJ, Zuschratter W (2002) Cell-type specific alterations of cortical interneurons in schizophrenic patients. Neuroreport 13:713–717

    Article  PubMed  Google Scholar 

  • Kaplan DR, Stephens RM (1994) Neurotrophin signal transduction by the Trk receptor. J Neurobiol 25:1404–1417

    Article  CAS  PubMed  Google Scholar 

  • Kasai A, Shima T, Okada M (2005) Role of Src family tyrosine kinases in the down-regulation of epidermal growth factor signaling in PC12-cells. Genes Cells 10:1175–1187

    Article  CAS  PubMed  Google Scholar 

  • Khandaker GM, Zimbron J, Lewis G, Jones PB (2013) Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies. Psychol Med 43:239–257

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    Article  CAS  PubMed  Google Scholar 

  • Levi A, Biocca S, Cattaneo A, Calissano P (1988) The mode of action of nerve growth factor in PC12-cells. Mol Neurobiol 2:201–226

    Article  CAS  PubMed  Google Scholar 

  • Lu XH, Dwyer DS (2005) Second-generation antipsychotic drugs, olanzapine, quetiapine, and clozapine enhance neurite outgrowth in PC12-cells via PI3K/AKT, ERK, and pertussis toxin-sensitive pathways. J Mol Neurosci 27:43–64

    Article  CAS  PubMed  Google Scholar 

  • Martinotti G, Di Iorio G, Marini S, Ricci V, De Berardis D, Di Giannantonio M (2012) Nerve growth factor and brain-derived neurotrophic factor concentrations in schizophrenia: a review. J Biol Regul Homeost Agents 26:347–356

    CAS  PubMed  Google Scholar 

  • Meltzer HY, Stahl SM (1976) The dopamine hypothesis of schizophrenia: a review. Schizophr Bull 2:19–76

    Article  CAS  PubMed  Google Scholar 

  • Moran AP, Prendergast MM, Appelmelk BJ (1996) Molecular mimicry of host structures by bacterial lipopolysaccharides and its contribution to disease. FEMS Immunol Med Microbiol 16:105–115

    Article  CAS  PubMed  Google Scholar 

  • Muldoon LL, Alvarez JI, Begley DJ, Boado RJ, Del Zoppo GJ, Doolittle ND, Engelhardt B, Hallenbeck JM, Lonser RR, Ohlfest JR, Prat A, Scarpa M, Smeyne RJ, Drewes LR, Neuwelt EA (2013) Immunologic privilege in the central nervous system and the blood–brain barrier. J Cereb Blood Flow Metab 33:13–21

    Article  CAS  PubMed  Google Scholar 

  • Müller N, Ackenheil M (1995) Immunoglobulin and albumin content of cerebrospinal fluid in schizophrenic patients: relationship to negative symptomatology. Schizophr Res 14:223–228

    Article  PubMed  Google Scholar 

  • Murray RM, O’Callaghan E, Castle DJ, Lewis SW (1992) A neurodevelopmental approach to the classification of schizophrenia. Schizophr Bull 18:319–332

    Article  CAS  PubMed  Google Scholar 

  • Ng YP, Cheung ZH, Ip NY (2006) STAT3 as a downstream mediator of Trk signaling and functions. J Biol Chem 281:15636–15644

    Article  CAS  PubMed  Google Scholar 

  • Nord M, Farde L (2011) Antipsychotic occupancy of dopamine receptors in schizophrenia. CNS Neurosci Ther 17:97–103

    Article  PubMed  Google Scholar 

  • Pugazhenthi S, Boras T, O’Connor D, Meintzer MK, Heidenreich KA, Reusch JE (1999) Insulin-like growth factor I-mediated activation of the transcription factor cAMP response element-binding protein in PC12-cells. Involvement of p38 mitogen-activated protein kinase-mediated pathway. J Biol Chem 274:2829–2837

    Article  CAS  PubMed  Google Scholar 

  • Rosenstein NE, Perkins BA, Stephens DS, Popovic T, Hughes JM (2001) Meningococcal disease. N Engl J Med 344:1378–1388

    Article  CAS  PubMed  Google Scholar 

  • Selemon LD, Goldman-Rakic PS (1999) The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry 45:17–25

    Article  CAS  PubMed  Google Scholar 

  • Selemon LD, Rajkowska G, Goldman-Rakic PS (1995) Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry 52:805–818

    Article  CAS  PubMed  Google Scholar 

  • Selemon LD, Rajkowska G, Goldman-Rakic PS (1998) Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: application of a three dimensional, stereologic counting method. J Comp Neurol 392:402–412

    Article  CAS  PubMed  Google Scholar 

  • Selemon LD, Mrzljak J, Kleinman JE, Herman MM, Goldman-Rakic PS (2003) Regional specificity in the neuropathologic substrates of schizophrenia: a morphometric analysis of Broca’s area 44 and area 9. Arch Gen Psychiatry 60:69–77

    Article  PubMed  Google Scholar 

  • Sofroniew MV, Howe CL, Mobley WC (2001) Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci 24:1217–1281

    Article  CAS  PubMed  Google Scholar 

  • Sørensen HJ, Mortensen EL, Reinisch JM, Mednick SA (2009) Association between prenatal exposure to bacterial infection and risk of schizophrenia. Schizophr Bull 35:631–637

    Article  PubMed  Google Scholar 

  • Stephens DS, Greenwood B, Brandtzaeg P (2007) Epidemic meningitis, meningococcaemia, and Neisseria meningitidis. Lancet 369:2196–2210

    Article  PubMed  Google Scholar 

  • Swedo SE, Leonard HL, Garvey M, Mittleman B, Allen AJ, Perlmutter S, Lougee L, Dow S, Zamkoff J, Dubbert BK (1998) Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 155:264–271

    CAS  PubMed  Google Scholar 

  • Tandon R, Nasrallah HA, Keshavan MS (2009) Schizophrenia, “just the facts” 4. Clinical features and conceptualization. Schizophr Res 110:1–23

    Article  PubMed  Google Scholar 

  • Ulrich S, Neuhof S, Braun V, Meyer FP (1998) Therapeutic window of serum haloperidol concentration in acute schizophrenia and schizoaffective disorder. Pharmacopsychiatry 31:163–169

    Article  CAS  PubMed  Google Scholar 

  • Van Horn JD, McManus IC (1992) Ventricular enlargement in schizophrenia. A meta-analysis of studies of the ventricle:brain ratio (VBR). Br J Psychiatry 160:687–697

    Article  PubMed  Google Scholar 

  • Vasic N, Connemann BJ, Wolf RC, Tumani H, Brettschneider J (2012) Cerebrospinal fluid biomarker candidates of schizophrenia: where do we stand? Eur Arch Psychiatry Clin Neurosci 262:375–391

    Article  PubMed  Google Scholar 

  • Wang H, Duan X, Ren Y, Liu Y, Huang M, Liu P, Wang R, Gao G, Zhou L, Feng Z, Zheng W (2013) FoxO3a negatively regulates nerve growth factor-induced neuronal differentiation through inhibiting the expression of neurochondrin in PC12-cells. Mol Neurobiol 47:24–36

    Article  CAS  PubMed  Google Scholar 

  • Wen Q, Duan X, Liao R, Little P, Gao G, Jiang H, Lalit S, Quirion R, Zheng W (2011) Characterization of intracellular translocation of Forkhead transcription factor O (FoxO) members induced by NGF in PC12-cells. Neurosci Lett 498:31–36

    Article  CAS  PubMed  Google Scholar 

  • Woods BT, Ward KE, Johnson EH (2005) Meta-analysis of the time-course of brain volume reduction in schizophrenia: implications for pathogenesis and early treatment. Schizophr Res 73:221–228

    Article  PubMed  Google Scholar 

  • Wright IC, Rabe-Hesketh S, Woodruff PW, David AS, Murray RM, Bullmore ET (2000) Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 157:16–25

    CAS  PubMed  Google Scholar 

  • Wu YY, Bradshaw RA (1996) Induction of neurite outgrowth by interleukin-6 is accompanied by activation of Stat3 signaling pathway in a variant PC12 cell (E2) line. J Biol Chem 271:13023–13032

    Article  CAS  PubMed  Google Scholar 

  • Zakharenko OM, Kliushnik TP, Kozlova IA, Kozlovskaia GV, Danilovskaia EV, Bashina VM, Simashkova VM, Goriunova AV, Kalinina MA (1999) Nerve growth factor auto-antibodies in the sera of mothers of schizophrenic children and children from high risk group. Zh Nevrol Psikhiatr Im S S Korsakova 99:44–46

    CAS  PubMed  Google Scholar 

  • Zhou L, Too HP (2011) Mitochondrial localized STAT3 is involved in NGF induced neurite outgrowth. Plops One 6(e21680):1–13

    Google Scholar 

Download references

Acknowledgments

I would like to thank the Medical Faculty of the University of Göttingen (UMG) for their persistent and reliable support of my work.

Conflict of Interest

The author declares no competing financial interests

Author information

Authors and Affiliations

  1. Institute for Neuroanatomy, Universitary Medicine Göttingen, Kreuzbergring 36, 37075, Göttingen, Germany

    B. Reuss

Authors
  1. B. Reuss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B. Reuss.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reuss, B. Antibodies Directed to Neisseria gonorrhoeae Impair Nerve Growth Factor-Dependent Neurite Outgrowth in Rat PC12 Cells. J Mol Neurosci 52, 353–365 (2014). https://doi.org/10.1007/s12031-013-0156-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-013-0156-8

Keywords

Search

Navigation