Abstract
Neurogenesis occurs in dentate gyrus of adult hippocampus under the influence of various mitogenic factors. Growth factors besides instigating the proliferation of neuronal progenitor cells (NPCs) in dentate gyrus, also supports their differentiation to cholinergic neurons. In the present study, an attempt has been made to investigate the neurotrophic effect of bFGF in Kainic acid (KA) induced cognitive dysfunction in rats. Stereotaxic lesioning using (KA) was performed in hippocampal CA3 region of rat’s brain. Four-weeks post lesioning rats were assessed for impairment in learning and memory using Y maze followed by bFGF infusion in dentate gyrus region. The recovery was evaluated after bFGF infusion using neurochemical, neurobehavioural and immunohistochemical approaches and compared with lesioned group. Significant impairment in learning and memory (P < 0.01) observed in lesioned animals, four weeks post lesioning exhibited significant restoration (P < 0.001) following bFGF infusion twice at one and four week post lesion. The bFGF infused animals exhibited recovery in hippocampus cholinergic (76%)/ dopaminergic (46%) receptor binding and enhanced Choline acetyltransferase (ChAT) immunoreactivity in CA3 region. The results suggest restorative potential of bFGF in cognitive dysfunctions, possibly due to mitogenic effect on dentate gyrus neurogenic area leading to generation and migration of newer cholinergic neurons.
Similar content being viewed by others
References
Kempermann G, Wiskott L, Gage FH (2004) Functional signicance of adult neurogenesis. Curr Opin Neurobiol 14:186–191
Abrous DN, Koehl M, Moal ML (2005) Adult neurogenesis: from precursors to network and physiology. Physiol Rev 85:523–569
Doetsch F, Hen R (2005) Young and excitable: the function of new neurons in the adult mammalian brain. Curr Opin Neurobiol 15:121–128
Rosato SM, Cattaneo A, Cherubini E (2006) Nicotine-induced enhancement of synaptic plasticity at CA3–CA1 synapses requires GABAergic interneurons in adult anti-NGF mice. J Physiol 576:361–377
Row BW, Kheirandish L, Cheng Y, Rowell PP, Gozal D (2007) Impaired spatial working memory and altered choline acetyltransferase (ChAT) immunoreactivity and nicotinic receptor binding in rats exposed to intermittent hypoxia during sleep. Behav Brain Res 177:308–314
Auls DS, Kornecook TJ, Bastianetto S, Quirion R (2002) Alzheimer’s disease and the basal forebrain cholinergic system: relation to β amyloid peptides, cognition, and treatment strategies. Prog Neurobiol 68:209–245
Kar S, Slowikowski SP, Westaway D, Mount HT (2004) Interactions between beta-amyloid and central cholinergic neurons: implications for Alzheimer’s disease. J Psychiatry Neurosci 29:427–441
Chun SK, Sun W, Park JJ, Jung MW (2006) Enhanced proliferation of progenitor cells following long-term potentiation induction in the rat dentate gyrus. Neurobiol Learn Mem 86:322–329
Shimazu K, Zhao M, Sakata K, Akbarian S, Bates B, Jaenisch R (2006) NT-3 facilitates hippocampal plasticity and learning and memory by regulating neurogenesis. Learn Mem 13:307–315
Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317
Gould E, Gross CG (2002) Neurogenesis in adult mammals: some progress and problems. J Neurosci 22:619–623
Gross CG (2000) Neurogenesis in the adult brain: death of a dogma. Nat Rev Neurosci 1:67–73
Feng R, Rampon C, Tang YP, Shrom D, Jin J, Kyin M, Sopher B, Miller MW, Ware CB, Martin GM, Kim SH, Langdon RB, Sisodia SS, Tsien JZ (2001) Deficient neurogenesis in forebrain specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron 32:911–926
Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302:1760–1765
Monje ML, Mizumatsum S, Fike JR, Palmer TD (2002) Irradiation induces neural precursor-cell dysfunction. Nat Med 8:955–962
Monje ML, Palmer T (2003) Radiation injury and neurogenesis. Curr Opin Neurol 16:129–134
Gray WP, Sundstrom LE (1998) Kainic acid increases the proliferation of granule cell progenitors in the dentate gyrus of the adult rat. Brain Res 790:52–59
Choi YS, Lee MY, Sung KW, Jeong SW, Choi JS, Park HJ, Kim ON, Lee SB, Kim SY (2003) Regional differences in enhanced neurogenesis in the dentate gyrus of adult rats after transient forebrain ischemia. Mol Cells 16:232–238
Felling RJ, Levison SW (2003) Enhanced neurogenesis following stroke. J Neurosci Res 73:277–283
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
Nakagawa E, Aimi Y, Yasuhara O, Tooyama I, Shimada M, Mc Geer PL, Kimura H (2000) Enhancement of progenitor cell division in the dentate gyrus triggered by initial limbic seizures in rat models of epilepsy. Epilepsia 41:10–18
Dinocourt CL, Gallagher SE, Thompson SM (2006) Injury-induced axonal sprouting in the hippocampus is initiated by activation of trkB receptors. Euro J Neurosci 24:1857–1866
Ikeda T, Koo H, Xia YX, Ikenoue T, Choi BH (2002) Bimodal upregulation of glial cell line-derived neurotrophic factor (GDNF) in the neonatal rat brain following ischemic/hypoxic injury. Int J Dev Neurosci 20:555–562
Shetty AK, Zaman V, Shetty GA (2003) Hippocampal neurotrophin levels in a kainate model of temporal lobe epilepsy: a lack of correlation between brain-derived neurotrophic factor content and progression of aberrant dentate mossy fiber sprouting. J Neurochem 87:147–159
Rola R, Mizumatsu S, Otsuka S, Morhardt DR, Noble-Haeusslein LJ, Fishman K, Potts MB, Fike JR (2006) Alterations in hippocampal neurogenesis following traumatic brain injury in mice. Exp Neurol 202:189–199
Chaturvedi RK, Shukla S, Seth K, Agrawal AK (2005) Nerve growth factor increases survival of dopaminergic graft, rescue nigral dopaminergic neurons and restores functional deficits in rat model of Parkinson’s disease. Neurosci Lett 398:44–49
Sun Y, Jin K, Childs JT, Xie L, Mao XO (2006) Vascular endothelial growth factor-B (VEGFB) stimulates neurogenesis: evidence from knockout mice and growth factor administration. Dev Biol 289:329–335
Youssoufian M, Walmsley B (2007) Brain-derived neurotrophic factor modulates cell excitability in the mouse medial nucleus of the trapezoid body. Eur J Neurosci 25:1647–1652
Yoshimura S, Takagi Y, Harada J, Teramoto TS, Thomas S, Waeber C, Bakowska JC, Xandra O, Breakefield, Moskowitz MA (2001) FGF-2 regulation of neurogenesis in adult hippocampus after brain injury. PNAS 98:5874–5879
Jin K, LaFevre- BM, Sun Y, Chen S, Gafni J, Crippen D, Logvinova A, Ross CA, Greenberg DA, Ellerby LM (2005) FGF-2 promotes neurogenesis and neuroprotection and prolongs survival in a transgenic mouse model of Huntington’s disease. Proc Natl Acad Sci 102:17889–17890
Spencer B, Agarwala S, Gentry L, Brandt CR (2001) HSV-1 vector-delivered FGF2 to the retina is neuroprotective but does not preserve functional responses. Mol Ther 3:746–756
Machon O, Backman M, Krauss S, Kozmik Z (2005) the cellular fate of cortical progenitors is not maintained in neurosphere cultures. Mol Cell Neurosci 30:388–397
Fagan AM, Suhr ST, Lucidi-Phillipi AA, Peterson DA, Holtzman DM, Gage FH (1997) Endogenous FGF-2 is important for cholinergic sprouting in the denervated hippocampus. J Neurosci 1:2499–2511
Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, 4th edn. Academic Press, California, USA
Zaman V, Shetty AK (2001) Fetal hippocampal ca3 cell grafts transplanted to lesioned ca3 region of the adult hippocampus exhibit long-term survival in a rat model of temporal lobe epilepsy. Neurobio Dis 8:942–952
Manfred Krug, Rudolf Brödemann, Renate Matthies, Heinz Rüthrich, Maria Wagner (2001) Activation of the dentate gyrus by stimulation of the contralateral perforant pathway: evoked potentials and long-term potentiation after ipsi- and contralateral induction. Hippocampus 11:157–167
Vorobyova V, Schibaev N, Kovalev G, Alzheimerd C (2005) Effects of neurotransmitter agonists on electrocortical activity in the rat kainate model of temporal lobe epilepsy and the modulatory action of basic fibroblast growth factor. Brain Res 1051:123–136
Yoshimura S, Teramoto T, Whalen MJ, Irizarry MC, Takagi Y, Jun Harada JQ, Waeber C, Xandra OB, Moskowitz MA (2003) FGF-2 regulates neurogenesis and degeneration in the dentate gyrus after traumatic brain injury in mice. J Clin Invest 112:1202–1210
Adhami VM, Husain R, Husain R, Seth PK (1996) Influence of iron deficiencies and lead treatment on behaviour and cerebellar and hippocampal polyamine levels in neonatal rats. Neurochem Res 21:915–922
Agrawal AK, Squib RE, Bondy SC (1981) Effect of acrylamide treatment upon dopamine receptor binding. Toxicol Appl Pharmacol 58:89–99
Lowry OH, Rosenburg NJ, Farr AL, Randall RJ (1951) Protein measurement by Folin phenol reagent. J Biol Chem 193:165–175
Barone S, Tandon P, McGinty JF, Tilson HA (1991) The effect of NGF and fetal cell transplantation on spatial learning after intra-dentate administration of colchicines. Exp Neurol 114:351–363
Agrawal AK, Shukla S, Chaturvedi RK, Seth K, Srivastava N, Ahmad A, Seth PK (2004) Olfactory ensheathing cell transplantation restores functional deficits in rat model of Parkinson’s disease: a cotransplantation approach with fetal ventral mesencephalic cells. Neurobiol Dis 16:516–526
Roy TS, Seidler FJ, Slotkin TA (2002) Prenatal nicotine exposure evokes alterations of cell structure in hippocampus and somatosensory cortex. J Pharmacol Exp Ther 300:124–133
Roy TS, Sharma V, Seidler FJ, Slotkin TA (2005) Quantitative morphological assessment reveals neuronal and glial deficits in hippocampus after a brief subtoxic exposure to chlorpyrifos in neonatal rats. Brain Res Dev Brain Res 155:71–80
Bellucci A, Luccarini I, Scali C, Costanza P, Giovannini MG, Casamenti PF (2006) Cholinergic dysfunction, neuronal damage and axonal loss in TgCRND8 mice. Neuro Dis 23:260–272
Bauer S, Patterson PH (2006) Leukemia inhibitory factor promotes neural stem cell self-renewal in the adult brain. J Neurosci 26:12089–12099
Leker RR, Soldner F, Velasco I, Gavin DK, Androutsellis-TA, McKay RD (2007) Long-lasting regeneration after ischemia in the cerebral cortex. Stroke 38:153–161
Broughton SK, Chen H, Riddle A, Kuhn SE, Nagalla S, Roberts Jr, Back SA (2007) Large-scale generation of highly enriched neural stem-cell-derived oligodendroglial cultures: maturation-dependent differences in insulin- like growth factor-mediated signal transduction. J Neurochem 100:628–638
Shetty AK, Rao MS, Hattiangady B, Zaman V, Shetty GA (2004) Hippocampal neurotrophin levels after injury: relationship to the age of the hippocampus at the time of injury. J Neurosci Res 78:520–532
Ford-Perriss M, Abud H, Murphy M (2001) Fibroblast growth factors in the developing central nervous system. Clin Exp Pharmacol Physiol 28:493–503
Tureyen K, Vemuganti R, Bowen KK, Sailor KA, Dempsey RJ (2005) EGF and FGF-2 infusion increases post-ischemic neural progenitor cell proliferation in the adult rat brain. Neurosurgery 57:1254–1263
Maric D, Fiorio PA, Chang YH, Barker JL (2007) Self-renewing and differentiating properties of cortical neural stem cells are selectively regulated by basic fibroblast growth factor (FGF) signaling via specific FGF receptors. J Neurosci 27:1836–1852
Ramirez JJ, Finklestein SP, Keller J, Abrams W, George MN, Parakh T (1999) Basic fibroblast growth factor enhances axonal sprouting after cortical injury in rats. Neuroreport 10:1201–1204
Smith C, Berry M, Clarke WE, Logan A (2001) Differential expression of fibroblast growth factor-2 and fibroblast growth factor receptor 1 in a scarring and nonscarring model of CNS injury in the rat. Eur J Neurosci 13:443–456
Hagood SK, McGinn MJ, Sun D, Colello RJ (2006) characterizes the mitogenic effect of basic fibroblast growth factor in the adult rat striatum. J Neurotrauma 23:205–215
Otmakhova NA, Lisman JE (1998) D1/D5 dopamine receptors inhibit depotentiation at ca1 synapses via camp-dependent mechanism. J Neurosci 18:1270–1279
Laplante F, Sibley DR, Quirion R (2004) Reduction in acetylcholine release in the hippocampus of dopamine D5 receptor-deficient mice. Neuropsychopharm 29:1620–1627
Otmakhova NA, Lisman JE (1996) D1/D5 dopamine receptor activation increases the magnitude of early long- term potentiation at CA1 hippocampal synapses. J Neurosci 16:7478–7486
Lisman JE, Otmakhova NA (2001) Storage, recall and novelty detection of sequences by the hippocampus; elaborating on the Socratic model to account for normal and aberrant effects of dopamine. Hippocampus 11:551–568
Acknowledgments
We are grateful to Dr. C.M. Gupta, Director, and ITRC for his continuous support during this study. Nishi Srivastava is recipient of Senior Research Fellowship from ICMR, New Delhi. K. Seth is a recipient of WOS (Women Scientist Award) from Department of Science and Technology (DST), New Delhi. Technical assistance of Mr. Kailash Chandra is gratefully acknowledged.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Srivastava, N., Seth, K., Srivastava, N. et al. Functional Restoration Using Basic Fibroblast Growth Factor (bFGF) Infusion in Kainic Acid Induced Cognitive Dysfunction in Rat: Neurobehavioural and Neurochemical Studies. Neurochem Res 33, 1169–1177 (2008). https://doi.org/10.1007/s11064-007-9478-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-007-9478-7