Abstract
Entorhinal cortex lesions have been established as a model for hippocampal deafferentation and have provided valuable information about the mechanisms of synapse reorganization and plasticity. Although several molecules have been proposed to contribute to these processes, the role of Wnt signaling components has not been explored, despite the critical roles that Wnt molecules play in the formation and maintenance of neuronal and synaptic structure and function in the adult brain. In this work, we assessed the reorganization process of the dentate gyrus (DG) at 1, 3, 7, and 30 days after an excitotoxic lesion in layer II of the entorhinal cortex. We found that cholinergic fibers sprouted into the outer molecular layer of the DG and revealed an increase of the developmental regulated MAP2C isoform 7 days after lesion. These structural changes were accompanied by the differential regulation of the Wnt signaling components Wnt7a, Wnt5a, Dkk1, and Sfrp1 over time. The progressive increase in the downstream Wnt-regulated elements, active-β-catenin, and cyclin D1 suggested the activation of the canonical Wnt pathway beginning on day 7 after lesion, which correlates with the structural adaptations observed in the DG. These findings suggest the important role of Wnt signaling in the reorganization processes after brain lesion and indicate the modulation of this pathway as an interesting target for neuronal tissue regeneration.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Becker D, Zahn N, Deller T, Vlachos A (2013) Tumor necrosis factor alpha maintains denervation-induced homeostatic synaptic plasticity of mouse dentate granule cells. Front Cell Neurosci 7:257. https://doi.org/10.3389/fncel.2013.00257
Berling B, Wille H, Röll B et al (1994) Phosphorylation of microtubule-associated proteins MAP2a, b and MAP2c at Ser136 by proline-directed kinases in vivo and in vitro. Eur J Cell Biol 64:120–130
Budnik V, Salinas PC (2011) Wnt signaling during synaptic development and plasticity. Curr Opin Neurobiol 21:151–159. https://doi.org/10.1016/j.conb.2010.12.002
Buechling T, Boutros M (2011) Wnt signaling. Signaling at and above the receptor level. In: Current topics in developmental biology. Academic Press, San Diego, pp 21–53
Caricasole A, Copani A, Caraci F et al (2004) Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer’s brain. J Neurosci 24:6021–6027. https://doi.org/10.1523/JNEUROSCI.1381-04.2004
Cerpa W, Godoy JA, Alfaro I et al (2008) Wnt-7a modulates the synaptic vesicle cycle and synaptic transmission in hippocampal neurons. J Biol Chem 283:5918–5927. https://doi.org/10.1074/jbc.M705943200
Chao LL, Mueller SG, Buckley ST et al (2010) Evidence of neurodegeneration in brains of older adults who do not yet fulfill MCI criteria. Neurobiol Aging 31:368–377. https://doi.org/10.1016/j.neurobiolaging.2008.05.004
Chen C-M, Orefice LL, Chiu S-L et al (2017) Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice. Proc Natl Acad Sci U S A 114:E619–E628. https://doi.org/10.1073/pnas.1615792114
Ciani L, Salinas PC (2005) WNTs in the vertebrate nervous system: from patterning to neuronal connectivity. Nat Rev Neurosci 6:351–362. https://doi.org/10.1038/nrn1665
Ciani L, Krylova O, Smalley MJ et al (2004) A divergent canonical WNT-signaling pathway regulates microtubule dynamics. J Cell Biol 164:243–253. https://doi.org/10.1083/jcb.200309096
Ciani L, Boyle KAKA, Dickins E et al (2011) Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca2+/Calmodulin-dependent protein kinase II. Proc Natl Acad Sci 108:10732–10737. https://doi.org/10.1073/pnas.1018132108
Conner JM, Varon S (1994) Nerve growth factor influences the distribution of sympathetic sprouting into the hippocampal formation by implanted superior cervical ganglia. Exp Neurol 130:15–23. https://doi.org/10.1006/exnr.1994.1180
De Ferrari GV, Inestrosa NC (2000) Wnt signaling function in Alzheimer’s disease. Brain Res Brain Res Rev 33:1–12
De Ferrari GV, Chacón MA, Barría MI et al (2003) Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils. Mol Psychiatry 8:195–208. https://doi.org/10.1038/sj.mp.4001208
Dehn D, Burbach GJ, Schäfer R, Deller T (2006) NG2 upregulation in the denervated rat fascia dentata following unilateral entorhinal cortex lesion. Glia 53:491–500. https://doi.org/10.1002/glia.20307
DeKosky ST, Scheff SW, Styren SD (1996) Structural correlates of cognition in dementia: quantification and assessment of synapse change. Neurodegeneration 5:417–421
Deller T, Frotscher M (1997) Lesion-induced plasticity of central neurons: sprouting of single fibres in the rat hippocampus after unilateral entorhinal cortex lesion. Prog Neurobiol 53:687–727. https://doi.org/10.1016/S0301-0082(97)00044-0
Deller T, Frotscher M, Nitsch R (1995) Morphological evidence for the sprouting of inhibitory commissural fibers in response to the lesion of the excitatory entorhinal input to the rat dentate gyrus. J Neurosci 15:6868–6878
Deller T, Haas CA, Frotscher M (2000) Reorganization of the rat fascia dentata after a unilateral entorhinal cortex lesion: role of the extracellular matrix. Ann N Y Acad Sci 911:207–220. https://doi.org/10.1111/j.1749-6632.2000.tb06728.x
Deller T, Haas CA, Frotscher M (2001) Sprouting in the hippocampus after entorhinal cortex lesion is layer-specific but not translaminar: which molecules may be involved? Restor Neurol Neurosci 19:159–167
Deller T, Del Turco D, Rappert A, Bechmann I (2007) Structural reorganization of the dentate gyrus following entorhinal denervation: species differences between rat and mouse. Prog Brain Res 163:501–528
Dehmelt L, Halpain S (2004) The MAP2/Tau family of microtubule-associated proteins. Genome Biol 6:204. https://doi.org/10.1186/gb-2004-6-1-204
Devanand DP, Pradhaban G, Liu X et al (2007) Hippocampal and entorhinal atrophy in mild cognitive impairment: prediction of Alzheimer disease. Neurology 68:828–836. https://doi.org/10.1212/01.wnl.0000256697.20968.d7
Diekmann S, Ohm TG, Nitsch R (1996) Long-lasting transneuronal changes in rat dentate granule cell dendrites after entorhinal cortex lesion. A combined intracellular injection and electron microscopy study. Brain Pathol 6:205–214; discussion 214–215
Farías GG, Alfaro IE, Cerpa W et al (2009) Wnt-5a/JNK signaling promotes the clustering of PSD-95 in hippocampal neurons. J Biol Chem 284:15857–15866. https://doi.org/10.1074/jbc.M808986200
Farías GG, Godoy JA, Cerpa W et al (2010) Wnt signaling modulates pre- and postsynaptic maturation: Therapeutic considerations. Dev Dyn 239:94–101. https://doi.org/10.1002/dvdy.22065
Garrido JL, Godoy JA, Alvarez A et al (2002) Protein kinase C inhibits amyloid beta peptide neurotoxicity by acting on members of the Wnt pathway. FASEB J 16:1982–1984. https://doi.org/10.1096/fj.02-0327fje
Gogolla N, Galimberti I, Deguchi Y, Caroni P (2009) Wnt signaling mediates experience-related regulation of synapse numbers and Mossy fiber connectivities in the adult hippocampus. Neuron 62:510–525. https://doi.org/10.1016/j.neuron.2009.04.022
Gomez-Isla T, West HL, Rebeck GW et al (1996) Clinical and pathological correlates of apolipoprotein E epsilon 4 in Alzheimer’s disease. Ann Neurol 39:62–70. https://doi.org/10.1002/ana.410390110
Gregory MA, Qi Y, Hann SR (2003) Phosphorylation by glycogen synthase kinase-3 controls c-Myc proteolysis and subnuclear localization. J Biol Chem 278:51606–51612. https://doi.org/10.1074/jbc.M310722200
Haas CA, Frotscher M, Deller T (1999a) Differential induction of c-Fos, c-Jun and Jun B in the rat central nervous system following unilateral entorhinal cortex lesion. Neuroscience 90:41–51. https://doi.org/10.1016/s0306-4522(98)00462-x
Haas CA, Rauch U, Thon N et al (1999b) Entorhinal cortex lesion in adult rats induces the expression of the neuronal chondroitin sulfate proteoglycan neurocan in reactive astrocytes. J Neurosci 19:9953–9963
Hales JB, Vincze JL, Reitz NT et al (2018) Recent and remote retrograde memory deficit in rats with medial entorhinal cortex lesions. Neurobiol Learn Mem 155:157–163. https://doi.org/10.1016/j.nlm.2018.07.013
Hall AC, Lucas FR, Salinas PC et al (2000) Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling King’s College London. Cell 100:525–535. https://doi.org/10.1016/S0092-8674(00)80689-3
He C-W, Liao C-P, Pan C-L (2018) Wnt signalling in the development of axon, dendrites and synapses. Open Biol 8:180116. https://doi.org/10.1098/rsob.180116
Hernández-Ortega K, Arias C (2012) ERK activation and expression of neuronal cell cycle markers in the hippocampus after entorhinal cortex lesion. J Neurosci Res 90:2116–2126. https://doi.org/10.1002/jnr.23106
Inestrosa NC, Arenas E (2010) Emerging roles of Wnts in the adult nervous system. Nat Rev Neurosci 11:77–86. https://doi.org/10.1038/nrn2755
Inestrosa NC, Toledo EM (2008) The role of Wnt signaling in neuronal dysfunction in Alzheimer’s Disease. Mol Neurodegener 3:9. https://doi.org/10.1186/1750-1326-3-9
Inestrosa N, De Ferrari GV, Garrido JL et al (2002) Wnt signaling involvement in beta-amyloid-dependent neurodegeneration. Neurochem Int 41:341–344. https://doi.org/10.1016/s0197-0186(02)00056-6
Kent WJ, Sugnet CW, Furey TS et al (2002) The human genome browser at UCSC. Genome Res 12:996–1006. https://doi.org/10.1101/gr.229102
Knowles WD (1992) Normal anatomy and neurophysiology of the hippocampal formation. J Clin Neurophysiol 9:252–263
Lee MY, Deller T, Kirsch M et al (1997) Differential regulation of ciliary neurotrophic factor (CNTF) and CNTF receptor alpha expression in astrocytes and neurons of the fascia dentata after entorhinal cortex lesion. J Neurosci 17:1137–1146
Lucas FR, Salinas PC (1997) WNT-7a induces axonal remodeling and increases synapsin I levels in cerebellar neurons. Dev Biol 192:31–44. https://doi.org/10.1006/dbio.1997.8734
Lucas FR, Goold RG, Gordon-Weeks PR, Salinas PC (1998) Inhibition of GSK-3beta leading to the loss of phosphorylated MAP-1B is an early event in axonal remodelling induced by WNT-7a or lithium. J Cell Sci 111(Pt 10):1351–1361
Mastroiacovo F, Busceti CL, Biagioni F et al (2009) Induction of the Wnt Antagonist, Dickkopf-1, Contributes to the Development of Neuronal Death in Models of Brain Focal Ischemia. J Cereb Blood Flow Metab 29:264–276. https://doi.org/10.1038/jcbfm.2008.111
Matthews DA, Cotman C, Lynch G (1976) An electron microscopic study of lesion-induced synaptogenesis in the dentate gyrus of the adult rat. I. Magnitude and time course of degeneration. Brain Res 115:1–21. https://doi.org/10.1016/0006-8993(76)90819-2
McLeod F, Bossio A, Marzo A et al (2018) Wnt signaling mediates LTP-dependent spine plasticity and AMPAR localization through frizzled-7 receptors. Cell Rep 23:1060–1071. https://doi.org/10.1016/j.celrep.2018.03.119
Ortiz-Matamoros A, Arias C (2018) Chronic infusion of Wnt7a, Wnt5a and Dkk-1 in the adult hippocampus induces structural synaptic changes and modifies anxiety and memory performance. Brain Res Bull 139:243–255. https://doi.org/10.1016/j.brainresbull.2018.03.008
Ortiz-Matamoros A, Arias C (2019) Differential changes in the number and morphology of the new neurons after chronic infusion of Wnt7a, Wnt5a, and Dkk-1 in the adult hippocampus in vivo. Anat Rec 302:1647–1657. https://doi.org/10.1002/ar.24069
Park M, Shen K (2012) WNTs in synapse formation and neuronal circuitry. EMBO J 31:2697–2704. https://doi.org/10.1038/emboj.2012.145
Paul CA, Beltz B (2010) Berger-Sweeney J (2010) Staining for acetylcholinesterase in brain sections. Cold Spring Harb Protoc. https://doi.org/10.1101/pdb.prot4806
Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates. Elsevier, New York
Phinney AL, Calhoun ME, Woods AG et al (2004) Stereological analysis of the reorganization of the dentate gyrus following entorhinal cortex lesion in mice. Eur J Neurosci 19:1731–1740. https://doi.org/10.1111/j.1460-9568.2004.03280.x
Poplawski GHD, Tranziska A-K, Leshchyns’ka I et al (2012) L1CAM increases MAP2 expression via the MAPK pathway to promote neurite outgrowth. Mol Cell Neurosci 50:169–178. https://doi.org/10.1016/j.mcn.2012.03.010
Rosen EY, Wexler EM, Versano R et al (2011) Functional genomic analyses identify pathways dysregulated by progranulin deficiency, implicating Wnt signaling. Neuron 71:1030–1042. https://doi.org/10.1016/j.neuron.2011.07.021
Sahores M, Gibb A, Salinas PC (2010) Frizzled-5, a receptor for the synaptic organizer Wnt7a, regulates activity-mediated synaptogenesis. Development 137:2215–2225. https://doi.org/10.1242/dev.046722
Salinas PC (2005) Signaling at the vertebrate synapse: new roles for embryonic morphogens? J Neurobiol 64:435–445. https://doi.org/10.1002/neu.20159
Salinas PC (2012) Wnt signaling in the vertebrate central nervous system: from axon guidance to synaptic function. Cold Spring Harb Perspect Biol 4:1–14. https://doi.org/10.1101/cshperspect.a008003
Salinas PC, Zou Y (2008) Wnt signaling in neural circuit assembly. Annu Rev Neurosci 31:339–358. https://doi.org/10.1146/annurev.neuro.31.060407.125649
Schmetsdorf S, Arnold E, Holzer M et al (2009) A putative role for cell cycle-related proteins in microtubule-based neuroplasticity. Eur J Neurosci 29:1096–1107. https://doi.org/10.1111/j.1460-9568.2009.06661.x
Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3:1101–1108. https://doi.org/10.1038/nprot.2008.73
Stoub TR, Rogalski EJ, Leurgans S et al (2010) Rate of entorhinal and hippocampal atrophy in incipient and mild AD: relation to memory function. Neurobiol Aging 31:1089–1098. https://doi.org/10.1016/j.neurobiolaging.2008.08.003
Tang S-J (2007) The synaptic Wnt signaling hypothesis. Synapse 61:866–868. https://doi.org/10.1002/syn.20434
Varela-Nallar L, Parodi J, Farías GG, Inestrosa NC (2012) Wnt-5a is a synaptogenic factor with neuroprotective properties against Aβ toxicity. Neurodegener Dis 10:23–26. https://doi.org/10.1159/000333360
Viereck C, Tucker RP, Matus A (1989) The adult rat olfactory system expresses microtubule-associated proteins found in the developing brain. J Neurosci 9:3547–3557
Wu X, Zhou S, Zhu N et al (2014) Resveratrol attenuates hypoxia/reoxygenation-induced Ca2+ overload by inhibiting the Wnt5a/Frizzled-2 pathway in rat H9c2 cells. Mol Med Rep 10:2542–2548. https://doi.org/10.3892/mmr.2014.2488
Xing Y, Zhang X, Zhao K et al (2012) Beneficial effects of sulindac in focal cerebral ischemia: A positive role in Wnt/β-catenin pathway. Brain Res 1482:71–80. https://doi.org/10.1016/j.brainres.2012.08.057
Zhang W, Shi Y, Peng Y et al (2018) Neuron activity-induced Wnt signaling up-regulates expression of brain-derived neurotrophic factor in the pain neural circuit. J Biol Chem 293:15641–15651. https://doi.org/10.1074/jbc.RA118.002840
Acknowledgements
The authors thank Nancy Monroy-Jaramillo, Miguel Tapia, and Patricia Ferrera for their technical assistance. L. García-Velázquez is a doctoral student from Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM) and received fellowship 254792 from CONACYT. This work was supported by PAPIIT, DGAPA IN202318, and Conacyt A1-S-9559.
Author information
Authors and Affiliations
Contributions
CA conceived and designed the study. LGV conducted experiments, data collection, and graphic material preparation. CA and LGV contributed to the analysis and interpretation of data, writing, and editing of the paper. All authors read and approved the final manuscript.
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
García-Velázquez, L., Arias, C. Differential Regulation of Wnt Signaling Components During Hippocampal Reorganization After Entorhinal Cortex Lesion. Cell Mol Neurobiol 41, 537–549 (2021). https://doi.org/10.1007/s10571-020-00870-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-020-00870-x