Skip to main content
SpringerLink
Log in

The role of autophagy in epileptogenesis and in epilepsy-induced neuronal alterations

  • Neurology and Preclinical Neurological Studies - Review article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

Recent evidence suggests that autophagy alterations are present in a variety of neurological disorders. These range from neurodegenerative diseases to acute neurological insults. Thus, despite a role of autophagy was investigated in a variety of neurological diseases, only recently these studies included epilepsy. This was fostered by the evidence that rapamycin, a powerful autophagy inducer, strongly modulates a variety of seizure models and epilepsies. These findings were originally interpreted as the results of the inhibition exerted by rapamycin on the molecular complex named “mammalian Target of Rapamycin” (mTOR). Recently, an increasing number of papers demonstrated that mTOR inhibition produces a strong activation of the autophagy machinery. In this way, it is now increasingly recognized that what was once defined as mTORpathy in epileptogenesis may be partially explained by abnormalities in the autophagy machinery. The present review features a brief introductory statement about the autophagy machinery and discusses the involvement of autophagy in seizures and epilepsies. An emphasis is posed on evidence addressing both pros and cons making it sometime puzzling and sometime evident, the role of autophagy in the epileptic brain.

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

Similar content being viewed by others

References

  • Aguado C, Sarkar S, Korolchuk VI, Criado O, Vernia S, Boya P, Sanz P, de Córdoba SR, Knecht E, Rubinsztein DC (2010) Laforin, the most common protein mutated in Lafora disease, regulates autophagy. Hum Mol Genet 19:2867–2876

    PubMed Central  CAS  PubMed  Google Scholar 

  • Amiri A, Cho W, Zhou J, Birnbaum SG, Sinton CM, McKay RM, Parada LF (2012) Pten deletion in adult hippocampal neural stem/progenitor cells causes cellular abnormalities and alters neurogenesis. J Neurosci 32:5880–5890

    CAS  PubMed  Google Scholar 

  • Anglade P, Vyas S, Javoy-Agid F, Herrero MT, Michel PP, Marquez J, Mouatt-Prigent A, Ruberg M, Hirsch EC, Agid Y (1997) Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 12:25–31

    CAS  PubMed  Google Scholar 

  • Aronson LI, Davenport EL, Mirabella F, Morgan GJ, Davies FE (2013) Understanding the interplay between the proteasome pathway and autophagy in response to dual PI3K/mTOR inhibition in myeloma cells is essential for their effective clinical application. Leukemia 27:2397–2403

    PubMed Central  CAS  PubMed  Google Scholar 

  • Baybis M, Yu J, Lee A, Golden JA, Weiner H, Mckhann G, Aronica E, Crino PB (2004) mTOR cascade activation distinguishes tubers from focal cortical dysplasia. Ann Neurol 56:478–487

    CAS  PubMed  Google Scholar 

  • Ben-Ari Y (1985) Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 14:375–403

    CAS  PubMed  Google Scholar 

  • Bernard A, Klionsky DJ (2014) Defining the membrane precursor supporting the nucleation of the phagophore. Autophagy 10:1–2

    CAS  PubMed  Google Scholar 

  • Buckmaster PS, Lew FH (2011) Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy. J Neurosci 31:2337–2347

    PubMed Central  CAS  PubMed  Google Scholar 

  • Buckmaster PS, Wen X (2011) Rapamycin suppresses axon sprouting by somatostatin interneurons in a mouse model of temporal lobe epilepsy. Epilepsia 52:2057–2064

    PubMed Central  CAS  PubMed  Google Scholar 

  • Buckmaster PS, Ingram EA, Wen X (2009) Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy. J Neurosci 29:8259–8269

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cabrera-López C, Martí T, Catalá V, Torres F, Mateu S, Ballarín J, Torra R (2012) Assessing the effectiveness of rapamycin on angiomyolipoma in tuberous sclerosis: a two years trial. Orphanet J Rare Dis 11(7):87

    Google Scholar 

  • Calderó J, Brunet N, Tarabal O, Piedrafita L, Hereu M, Ayala V, Esquerda JE (2010) Lithium prevents excitotoxic cell death of motoneurons in organotypic slice cultures of spinal cord. Neuroscience 165:1353–1369

    PubMed  Google Scholar 

  • Cao L, Xu J, Lin Y, Zhao X, Liu X, Chi Z (2009) Autophagy is upregulated in rats with status epilepticus and partly inhibited by vitamin E. Biochem Biophys Res Commun 379:949–953

    CAS  PubMed  Google Scholar 

  • Castino R, Lazzeri G, Lenzi P, Bellio N, Follo C, Ferrucci M, Fornai F, Isidoro C (2008) Suppression of autophagy precipitates neuronal cell death following low doses of methamphetamine. J Neurochem 106:1426–1439

    CAS  PubMed  Google Scholar 

  • Cecarini V, Bonfili L, Cuccioloni M, Mozzicafreddo M, Rossi G, Buizza L, Uberti D, Angeletti M, Eleuteri AM (2012) Crosstalk between the ubiquitin-proteasome system and autophagy in a human cellular model of Alzheimer’s disease. Biochim Biophys Acta 1822:1741–1751

    CAS  PubMed  Google Scholar 

  • Chachua T, Poon KL, Yum MS, Nesheiwat L, DeSantis K, Velíšková J, Velíšek L (2012) Rapamycin has age-, treatment paradigm-, and model-specific anticonvulsant effects and modulates neuropeptide Y expression in rats. Epilepsia 53:2015–2025

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chen R, Jin R, Wu L, Ye X, Yang Y, Luo K, Wang W, Wu D, Ye X, Huang L, Huang T, Xiao G (2011) Reticulon 3 attenuates the clearance of cytosolic prion aggregates via inhibiting autophagy. Autophagy 7:205–216

    CAS  PubMed  Google Scholar 

  • Chen L, Hu L, Dong JY, Ye Q, Hua N, Wong M, Zeng LH (2012) Rapamycin has paradoxical effects on S6 phosphorylation in rats with and without seizures. Epilepsia 53:2026–2033

    PubMed Central  CAS  PubMed  Google Scholar 

  • Criado O, Aguado C, Gayarre J, Duran-Trio L, Garcia-Cabrero AM, Vernia S, San Millán B, Heredia M, Romá-Mateo C, Mouron S, Juana-López L, Domínguez M, Navarro C, Serratosa JM, Sanchez M, Sanz P, Bovolenta P, Knecht E, Rodriguez de Cordoba S (2012) Lafora bodies and neurological defects in malin-deficient mice correlate with impaired autophagy. Hum Mol Genet 21:1521–1533

    CAS  PubMed  Google Scholar 

  • Crino PB, Miyata H, Vinters HV (2002) Neurodevelopmental disorders as a cause of seizures: neuropathologic, genetic, and mechanistic considerations. Brain Pathol 12:212–233

    CAS  PubMed  Google Scholar 

  • de Lanerolle NC, Lee TS, Spencer DD (2010) Astrocytes and epilepsy. Neurotherapeutics 7:424–438

    PubMed  Google Scholar 

  • Dengjel J, Høyer-Hansen M, Nielsen MO, Eisenberg T, Harder LM, Schandorff S, Farkas T, Kirkegaard T, Becker AC, Schroeder S, Vanselow K, Lundberg E, Nielsen MM, Kristensen AR, Akimov V, Bunkenborg J, Madeo F, Jäättelä M, Andersen JS (2012) Identification of autophagosome-associated proteins and regulators by quantitative proteomic analysis and genetic screens. Mol Cell Proteomics 11(M111):014035

    PubMed  Google Scholar 

  • Dudek FE, Clark S, Williams PA, Grabenstatter HL (2006) Kainate-induced status epilepticus: a chronic model of acquired epilepsy. In: Pitkänen A, Schwartzkroin PA, Moshé SL (eds) Models of seizures and epilepsy. Elsevier Academic, Amsterdam (ISBN: 978-0-12-088554-1)

  • Duran J, Gruart A, García-Rocha M, Delgado-García JM, Guinovart JJ (2014) Glycogen accumulation underlies neurodegeneration and autophagy impairment in Lafora disease. Hum Mol Genet 23:3147–3156

    CAS  PubMed  Google Scholar 

  • Ebrahimi-Fakhari D, McLean PJ, Unni VK (2012) Alpha-synuclein’s degradation in vivo: opening a new (cranial) window on the roles of degradation pathways in Parkinson disease. Autophagy 8:281–283

    PubMed Central  CAS  PubMed  Google Scholar 

  • Engelender S (2012) α-Synuclein fate: proteasome or autophagy? Autophagy 8:418–420

    CAS  PubMed  Google Scholar 

  • Ferrucci M, Pasquali L, Ruggieri S, Paparelli A, Fornai F (2008) Alpha-synuclein and autophagy as common steps in neurodegeneration. Parkinsonism Relat Disord 14(Suppl 2):S180–S184

    PubMed  Google Scholar 

  • Ferrucci M, Fulceri F, Toti L, Soldani P, Siciliano G, Paparelli A, Fornai F (2011) Protein clearing pathways in ALS. Arch Ital Biol 149:121–149

    PubMed  Google Scholar 

  • Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, Engel J Jr (2005) Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 46:470–472

    PubMed  Google Scholar 

  • Fornai F, Lenzi P, Gesi M, Ferrucci M, Lazzeri G, Busceti CL, Ruffoli R, Soldani P, Ruggieri S, Alessandri MG, Paparelli A (2003) Fine structure and biochemical mechanisms underlying nigrostriatal inclusions and cell death after proteasome inhibition. J Neurosci 23:8955–8966

    CAS  PubMed  Google Scholar 

  • Fornai F, Lenzi P, Gesi M, Ferrucci M, Lazzeri G, Capobianco L, de Blasi A, Battaglia G, Nicoletti F, Ruggieri S, Paparelli A (2004) Similarities between methamphetamine toxicity and proteasome inhibition. Ann N Y Acad Sci 1025:162–170

    CAS  PubMed  Google Scholar 

  • Fornai F, Soldani P, Lazzeri G, di Poggio AB, Biagioni F, Fulceri F, Batini S, Ruggieri S, Paparelli A (2005a) Neuronal inclusions in degenerative disorders. Do they represent static features or a key to understand the dynamics of the disease? Brain Res Bull 65:275–290

    CAS  PubMed  Google Scholar 

  • Fornai F, Schlüter OM, Lenzi P, Gesi M, Ruffoli R, Ferrucci M, Lazzeri G, Busceti CL, Pontarelli F, Battaglia G, Pellegrini A, Nicoletti F, Ruggieri S, Paparelli A, Südhof TC (2005b) Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc Natl Acad Sci USA 102:3413–3418

    PubMed Central  CAS  PubMed  Google Scholar 

  • Fornai F, Lazzeri G, Bandettini Di Poggio A, Soldani P, De Blasi A, Nicoletti F, Ruggieri S, Paparelli A (2006a) Convergent roles of alpha-synuclein, DA metabolism, and the ubiquitin-proteasome system in nigrostriatal toxicity. Ann N Y Acad Sci 1074:84–89

    CAS  PubMed  Google Scholar 

  • Fornai F, Ferrucci M, Gesi M, Bandettini di Poggio A, Giorgi FS, Biagioni F, Paparelli A (2006b) A hypothesis on prion disorders: are infectious, inherited, and sporadic causes so distinct? Brain Res Bull 69:95–100

    CAS  PubMed  Google Scholar 

  • Fornai F, Longone P, Cafaro L, Kastsiuchenka O, Ferrucci M, Manca ML, Lazzeri G, Spalloni A, Bellio N, Lenzi P, Modugno N, Siciliano G, Isidoro C, Murri L, Ruggieri S, Paparelli A (2008a) Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 105:2052–2057

    PubMed Central  CAS  PubMed  Google Scholar 

  • Fornai F, Longone P, Ferrucci M, Lenzi P, Isidoro C, Ruggieri S, Paparelli A (2008b) Autophagy and amyotrophic lateral sclerosis: the multiple roles of lithium. Autophagy 4:527–530

    CAS  PubMed  Google Scholar 

  • Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY, Curatolo P, de Vries PJ, Whittemore VH, Thiele EA, Ford JP, Shah G, Cauwel H, Lebwohl D, Sahmoud T, Jozwiak S (2013) Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 381:125–132

    CAS  PubMed  Google Scholar 

  • Fulceri F, Ferrucci M, Lazzeri G, Paparelli S, Bartalucci A, Tamburini I, Paparelli A, Fornai F (2011) Autophagy activation in glutamate-induced motor neuron loss. Arch Ital Biol 149:101–111

    PubMed  Google Scholar 

  • Gaitanis JN, Donahue J (2013) Focal cortical dysplasia. Pediatr Neurol 49:79–87

    PubMed  Google Scholar 

  • Galanopoulou AS, Gorter JA, Cepeda C (2012) Finding a better drug for epilepsy: the mTOR pathway as an antiepileptogenic target. Epilepsia 53:1119–1130

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ganesh S, Delgado-Escueta AV, Sakamoto T, Avila MR, Machado-Salas J, Hoshii Y, Akagi T, Gomi H, Suzuki T, Amano K, Agarwala KL, Hasegawa Y, Bai DS, Ishihara T, Hashikawa T, Itohara S, Cornford EM, Niki H, Yamakawa K (2002) Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice. Hum Mol Genet 11:1251–1262

    CAS  PubMed  Google Scholar 

  • García-Cabrero AM, Marinas A, Guerrero R, de Córdoba SR, Serratosa JM, Sánchez MP (2012) Laforin and malin deletions in mice produce similar neurologic impairments. J Neuropathol Exp Neurol 71:413–421

    PubMed  Google Scholar 

  • Garyali P, Siwach P, Singh PK, Puri R, Mittal S, Sengupta S, Parihar R, Ganesh S (2009) The malin–laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system. Hum Mol Genet 18:688–700

    CAS  PubMed  Google Scholar 

  • Garyali P, Segvich DM, DePaoli-Roach AA, Roach PJ (2014) Protein degradation and quality control in cells from Laforin and Malin knockout mice. J Biol Chem 289:20606–20614

    CAS  PubMed  Google Scholar 

  • Giorgi FS, Ferrucci M, Lazzeri G, Pizzanelli C, Lenzi P, Alessandrl MG, Murri L, Fornai F (2003) A damage to locus coeruleus neurons converts sporadic seizures into self-sustaining limbic status epilepticus. Eur J Neurosci 17:2593–2601

    PubMed  Google Scholar 

  • Giorgi FS, Bandettini di Poggio A, Battaglia G, Pellegrini A, Murri L, Ruggieri S, Paparelli A, Fornai F (2006) A short overview on the role of alpha-synuclein and proteasome in experimental models of Parkinson’s disease. J Neural Transm Suppl 70:105–109 (review)

    CAS  PubMed  Google Scholar 

  • Hartman AL, Santos P, Dolce A, Hardwick JM (2012) The mTOR inhibitor rapamycin has limited acute anticonvulsant effects in mice. PLoS ONE 7:e45156

    PubMed Central  CAS  PubMed  Google Scholar 

  • Heng K, Haney MM, Buckmaster PS (2013) High-dose rapamycin blocks mossy fiber sprouting but not seizures in a mouse model of temporal lobe epilepsy. Epilepsia 54:1535–1541

    PubMed Central  CAS  PubMed  Google Scholar 

  • Huang XL, Zhang H, Yang J, Wu J, McMahon J, Lin Y, Cao Z, Gruenthal M, Huang Y (2010) Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol Dis 40:193–199

    PubMed Central  CAS  PubMed  Google Scholar 

  • Jansen LA, Uhlmann EJ, Crino PB, Gutmann DH, Wong M (2005) Epileptogenesis and reduced inward rectifier potassium current in tuberous sclerosis complex-1-deficient astrocytes. Epilepsia 46:1871–1880

    CAS  PubMed  Google Scholar 

  • Jellinger KA, Stadelmann C (2000) Mechanisms of cell death in neurodegenerative disorders. J Neural Transm Suppl 59:95–114

    Google Scholar 

  • Klionsky DJ, Eskelinen EL, Deretic V (2014) Autophagosomes, phagosomes, autolysosomes, phagolysosomes, autophagolysosomes… wait, I’m confused. Autophagy 10:549–551

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kraft C, Peter M, Hofmann K (2010) Selective autophagy: ubiquitin-mediated recognition and beyond. Nat Cell Biol 12:836–841

    CAS  PubMed  Google Scholar 

  • Lasarge CL, Danzer SC (2014) Mechanisms regulating neuronal excitability and seizure development following mTOR pathway hyperactivation. Front Mol Neurosci 14(7):18

    Google Scholar 

  • Lenzi P, Marongiu R, Falleni A, Gelmetti V, Busceti CL, Michiorri S, Valente EM, Fornai F (2012) A subcellular analysis of genetic modulation of PINK1 on mitochondrial alterations, autophagy and cell death. Arch Ital Biol 150:194–217

    CAS  PubMed  Google Scholar 

  • Liberski PP, Sikorska B, Bratosiewicz-Wasik J, Gajdusek DC, Brown P (2004) Neuronal cell death in transmissible spongiform encephalopathies (prion diseases) revisited: from apoptosis to autophagy. Int J Biochem Cell Biol 36:2473–2490 (review)

    CAS  PubMed  Google Scholar 

  • Macias M, Blazejczyk M, Kazmierska P, Caban B, Skalecka A, Tarkowski B, Rodo A, Konopacki J, Jaworski J (2013) Spatiotemporal characterization of mTOR kinase activity following kainic acid induced status epilepticus and analysis of rat brain response to chronic rapamycin treatment. PLoS ONE 8:e64455

    PubMed Central  CAS  PubMed  Google Scholar 

  • Madeo F, Eisenberg T, Kroemer G (2009) Autophagy for the avoidance of neurodegeneration. Genes Dev 23:2253–2259

    PubMed Central  CAS  PubMed  Google Scholar 

  • Manning BD, Cantley LC (2003) Rheb fills a GAP between TSC and TOR. Trends Biochem Sci 28:573–576

    CAS  PubMed  Google Scholar 

  • Mazarati A, Bragin A, Baldwin R, Shin D, Wilson C, Sankar R, Naylor D, Engel J, Wasterlain CG (2002) Epileptogenesis after self-sustaining status epilepticus. Epilepsia 43 Suppl 5:74–80

    PubMed  Google Scholar 

  • McMahon J, Huang X, Yang J, Komatsu M, Yue Z, Qian J, Zhu X, Huang Y (2012) Impaired autophagy in neurons after disinhibition of mammalian target of rapamycin and its contribution to epileptogenesis. J Neurosci 32:15704–15714

    PubMed Central  CAS  PubMed  Google Scholar 

  • Miyahara H, Natsumeda M, Shiga A, Aoki H, Toyoshima Y, Zheng Y, Takeuchi R, Murakami H, Masuda H, Kameyama S, Izumi T, Fujii Y, Takahashi H, Kakita A (2013) Suppressed expression of autophagosomal protein LC3 in cortical tubers of tuberous sclerosis complex. Brain Pathol 23:254–262

    CAS  PubMed  Google Scholar 

  • Natale G, Pasquali L, Ruggieri S, Paparelli A, Fornai F (2008) Parkinson’s disease and the gut: a well known clinical association in need of an effective cure and explanation. Neurogastroenterol Motil 20:741–749

    CAS  PubMed  Google Scholar 

  • Nixon RA (2013) The role of autophagy in neurodegenerative disease. Nat Med 19:983–997

    CAS  PubMed  Google Scholar 

  • Ortolano S, Vieitez I, Agis-Balboa RC, Spuch C (2014) Loss of GABAergic cortical neurons underlies the neuropathology of Lafora disease. Mol Brain 7:7

    PubMed Central  PubMed  Google Scholar 

  • Orzi F, Casolla B, Rocchi R, Fornai F (2012) Prion-like mechanisms in epileptogenesis. Neurol Sci 34:1035–1108

    PubMed  Google Scholar 

  • Pan T, Kondo S, Le W, Jankovic J (2008) The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson’s disease. Brain 131(Pt 8):1969–1978

    PubMed  Google Scholar 

  • Pasquali L, Longone P, Isidoro C, Ruggieri S, Paparelli A, Fornai F (2009) Autophagy, lithium, and amyotrophic lateral sclerosis. Muscle Nerve 40:173–194

    CAS  PubMed  Google Scholar 

  • Pasquali L, Ruffoli R, Fulceri F, Pietracupa S, Siciliano G, Paparelli A, Fornai F (2010) The role of autophagy: what can be learned from the genetic forms of amyotrophic lateral sclerosis. CNS Neurol Disord Drug Target 9:268–278 (review)

    CAS  Google Scholar 

  • Petroi D, Popova B, Taheri-Talesh N, Irniger S, Shahpasandzadeh H, Zweckstetter M, Outeiro TF, Braus GH (2012) Aggregate clearance of α-synuclein in Saccharomyces cerevisiae depends more on autophagosome and vacuole function than on the proteasome. J Biol Chem 287:27567–27579

    PubMed Central  CAS  PubMed  Google Scholar 

  • Piredda S, Gale K (1985) A crucial epileptogenic site in the deep prepiriform cortex. Nature 317:623–625

    CAS  PubMed  Google Scholar 

  • Polajnar ML, Zerovnik E (2011) Impaired autophagy: a link between neurodegenerative diseases and progressive myoclonus epilepsies. Trends Mol Med 17:293–300

    PubMed  Google Scholar 

  • Puri R, Suzuki T, Yamakawa K, Ganesh S (2012) Dysfunctions in endosomal–lysosomal and autophagy pathways underlie neuropathology in a mouse model for Lafora disease. Hum Mol Genet 21:175–184

    PubMed  Google Scholar 

  • Qiao L, Zhang J (2009) Inhibition of lysosomal functions reduces proteasomal activity. Neurosci Lett 456:15–19

    CAS  PubMed  Google Scholar 

  • Raab-Graham KF, Haddick PC, Jan YN, Jan LY (2006) Activity- and mTOR-dependent suppression of Kv1.1 channel mRNA translation in dendrites. Science 314:144–148

    CAS  PubMed  Google Scholar 

  • Raffo E, Coppola A, Ono T, Briggs SW, Galanopoulou AS (2011) A pulse rapamycin therapy for infantile spasms and associated cognitive decline. Neurobiol Dis 43:322–329

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ramachandran N, Girard JM, Turnbull J, Minassian BA (2009) The autosomal recessively inherited progressive myoclonus epilepsies and their genes. Epilepsia 50(Suppl 5):29–36

    CAS  PubMed  Google Scholar 

  • Rattka M, Brandt C, Löscher W (2013) The intrahippocampal kainate model of temporal lobe epilepsy revisited: epileptogenesis, behavioral and cognitive alterations, pharmacological response, and hippocampal damage in epileptic rats. Epilepsy Res 103(2–3):135–152

    CAS  PubMed  Google Scholar 

  • Ravikumar B, Duden R, Rubinsztein DC (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 11:1107–1117

    CAS  PubMed  Google Scholar 

  • Riikonen R (2014) Recent advances in the pharmacotherapy of infantile spasms. CNS Drugs 28:279–290

    CAS  PubMed  Google Scholar 

  • Ryu HJ, Kim JE, Yeo SI, Kim DW, Kwon OS, Choi SY, Kang TC (2011a) F-actin depolymerization accelerates clasmatodendrosis via activation of lysosome-derived autophagic astroglial death. Brain Res Bull 85:368–373

    CAS  PubMed  Google Scholar 

  • Ryu HJ, Kim JE, Yeo SI, Kang TC (2011b) p65/RelA-Ser529 NF-κB subunit phosphorylation induces autophagic astroglial death (Clasmatodendrosis) following status epilepticus. Cell Mol Neurobiol 31:1071–1078

    CAS  PubMed  Google Scholar 

  • Sadler RM (2006) The syndrome of mesial temporal lobe epilepsy with hippocampal sclerosis: clinical features and differential diagnosis. Adv Neurol 97:27–37

    PubMed  Google Scholar 

  • Saitsu H, Nishimura T, Muramatsu K, Kodera H, Kumada S, Sugai K, Kasai-Yoshida E, Sawaura N, Nishida H, Hoshino A, Ryujin F, Yoshioka S, Nishiyama K, Kondo Y, Tsurusaki Y, Nakashima M, Miyake N, Arakawa H, Kato M, Mizushima N, Matsumoto N (2013) De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat Genet 45:445–449

    CAS  PubMed  Google Scholar 

  • Scantlebury MH, Galanopoulou AS, Chudomelova L, Raffo E, Betancourth D, Moshé SL (2010) A model of symptomatic infantile spasms syndrome. Neurobiol Dis 37:604–612

    PubMed Central  PubMed  Google Scholar 

  • Seifert G, Steinhäuser C (2013) Neuron-astrocyte signaling and epilepsy. Exp Neurol 244:4–10

    PubMed  Google Scholar 

  • Sha LZ, Xing XL, Zhang D, Yao Y, Dou WC, Jin LR, Wu LW, Xu Q (2012) Mapping the spatio-temporal pattern of the mammalian target of rapamycin (mTOR) activation in temporal lobe epilepsy. PLoS ONE 7:e39152

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shacka JJ, Lu J, Xie ZL, Uchiyama Y, Roth KA, Zhang J (2007) Kainic acid induces early and transient autophagic stress in mouse hippocampus. Neurosci Lett 414:57–60

    PubMed Central  CAS  PubMed  Google Scholar 

  • Silva JG, Mello LE (2000) The role of mossy cell death and activation of protein synthesis in the sprouting of dentate mossy fibers: evidence from calretinin and neo-timm staining in pilocarpine-epileptic mice. Epilepsia 41(Suppl 6):S18–S23

    PubMed  Google Scholar 

  • Singh PK, Singh S, Ganesh S (2012) The laforin–malin complex negatively regulates glycogen synthesis by modulating cellular glucose uptake via glucose transporters. Mol Cell Biol 32:652–663

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sisodiya SML, Fauser S, Cross JH, Thom M (2009) Focal cortical dysplasia type II: biological features and clinical perspectives. Lancet Neurol 8:830–843

    PubMed  Google Scholar 

  • Sloviter RS (2005) The neurobiology of temporal lobe epilepsy: too much information, not enough knowledge. C R Biol 328:143–153

    PubMed  Google Scholar 

  • Sloviter RS (2008) Hippocampal epileptogenesis in animal models of mesial temporal lobe epilepsy with hippocampal sclerosis: the importance of the “latent period” and other concepts. Epilepsia 49 Suppl 9:85–92

    PubMed  Google Scholar 

  • Sosunov AA, Wu X, McGovern RA, Coughlin DG, Mikell CB, Goodman RR, McKhann GM 2nd (2012) The mTOR pathway is activated in glial cells in mesial temporal sclerosis. Epilepsia 53 Suppl 1:78–86

    PubMed  Google Scholar 

  • Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J (2003) Tuberous sclerosis complex gene products, tuberin and hamartin, control mTOR signaling by acting as a GTPase activating protein complex toward Rheb. Curr Biol 13:1259–1268

    CAS  PubMed  Google Scholar 

  • Turnbull J, Epp JR, Goldsmith D, Zhao X, Pencea N, Wang P, Frankland PW, Ackerley CA, Minassian BA (2014) PTG protein depletion rescues malin-deficient Lafora disease in mouse. Ann Neurol 75:442–446

    CAS  PubMed  Google Scholar 

  • Turski L, Ikonomidou C, Turski WA, Bortolotto ZA, Cavalheiro EA (1989) Review: cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: a novel experimental model of intractable epilepsy. Synapse 3:154–171

    CAS  PubMed  Google Scholar 

  • Urushitani M, Kurisu J, Tsukita K, Takahashi R (2002) Proteasomal inhibition by misfolded mutant superoxide dismutase 1 induces selective motor neuron death in familial amyotrophic lateral sclerosis. J Neurochem 83:1030–1042

    CAS  PubMed  Google Scholar 

  • Valles-Ortega JL, Duran J, Garcia-Rocha M, Bosch C, Saez I, Pujadas L, Serafin A, Cañas X, Soriano E, Delgado-García JM, Gruart A, Guinovart JJ (2011) Neurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease. EMBO Mol Med 3:667–681

    PubMed Central  CAS  PubMed  Google Scholar 

  • Velísek L, Jehle K, Asche S, Velísková J (2007) Model of infantile spasms induced by N-methyl-d-aspartic acid in prenatally impaired brain. Ann Neurol 61:109–119

    PubMed  Google Scholar 

  • Viiri J, Amadio M, Marchesi N, Hyttinen JM, Kivinen N, Sironen R, Rilla K, Akhtar S, Provenzani A, D’Agostino VG, Govoni S, Pascale A, Agostini H, Petrovski G, Salminen A, Kaarniranta K (2013) Autophagy activation clears ELAVL1/HuR-mediated accumulation of SQSTM1/p62 during proteasomal inhibition in human retinal pigment epithelial cells. PLoS ONE 8:e69563

    PubMed Central  CAS  PubMed  Google Scholar 

  • Weston MC, Chen H, Swann JW (2012) Multiple roles for mammalian target of rapamycin signaling in both glutamatergic and GABAergic synaptic transmission. J Neurosci 32:11441–11452

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wyttenbach A, Carmichael J, Swartz J, Furlong RA, Narain Y, Rankin J, Rubinsztein DC (2000) Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington’s disease. Proc Natl Acad Sci USA 97:2898–2903

    PubMed Central  CAS  PubMed  Google Scholar 

  • Xilouri M, Brekk OR, Stefanis L (2013) α-Synuclein and protein degradation systems: a reciprocal relationship. Mol Neurobiol 47:537–551

    CAS  PubMed  Google Scholar 

  • Yang F, Yang YP, Mao CJ, Liu L, Zheng HF, Hu LF, Liu CF (2013) Crosstalk between the proteasome system and autophagy in the clearance of α-synuclein. Acta Pharmacol Sin 34:674–680

    PubMed Central  PubMed  Google Scholar 

  • Yasin SA, Ali AM, Tata M, Picker SR, Anderson GW, Latimer-Bowman E, Nicholson SL, Harkness W, Cross JH, Paine SM, Jacques TS (2013) mTOR-dependent abnormalities in autophagy characterize human malformations of cortical development: evidence from focal cortical dysplasia and tuberous sclerosis. Acta Neuropathol 126:207–218

    CAS  PubMed  Google Scholar 

  • Yuen AW, Sander JW (2014) Rationale for using intermittent calorie restriction as a dietary treatment for drug resistant epilepsy. Epilepsy Behav 33C:110–114

    Google Scholar 

  • Zeng LH, Rensing NR, Wong M (2009) The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J Neurosci 29:6964–6972

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhao W, Chuang SC, Bianchi R, Wong RK (2011) Dual regulation of fragile X mental retardation protein by group I metabotropic glutamate receptors controls translation-dependent epileptogenesis in the hippocampus. J Neurosci 31:725–734

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neurology Unit, Department of Clinical and Experimental Medicine, Pisa University Hospital, University of Pisa, Pisa, Italy

    Filippo Sean Giorgi

  2. Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

    Paola Lenzi & Francesco Fornai

  3. I.R.C.C.S. INM Neuromed, Pozzilli, Italy

    Francesca Biagioni, Alessandro Frati & Francesco Fornai

  4. University of Rome “Sapienza”, Rome, Italy

    Alessandro Frati

Authors
  1. Filippo Sean Giorgi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francesca Biagioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paola Lenzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alessandro Frati
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francesco Fornai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francesco Fornai.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Giorgi, F.S., Biagioni, F., Lenzi, P. et al. The role of autophagy in epileptogenesis and in epilepsy-induced neuronal alterations. J Neural Transm 122, 849–862 (2015). https://doi.org/10.1007/s00702-014-1312-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-014-1312-1

Keywords

Search

Navigation