Temporal lobe epilepsy (TE) is characterized by loss of hippocampal cells, often leading to hippocampal sclerosis, subsequent reorganization of the hippocampal network, and deficits in declarative memory. Despite a huge amount of experimental, preclinical, and clinical research, there is still limited understanding of the mechanisms underlying the development of TE. The dentate gyrus (DG) has been suggested to play a decisive role in the mechanisms of the development of this disease. The protective function of the DG, which is based on the low excitability of granule neurons and protects hippocampal pyramidal cells from hyperactivation under strong excitatory influences, is believed to be impaired in TE. Loss of mossy cells has been found in the hilus of the DG in patients with temporal lobe epilepsy. Some authors consider mossy cell vulnerability a critical factor in the development of TE: these neurons normally behave as circuit breakers, and their death breaks the natural neural network, leading to pathological activity. The present paper discusses changes in the morphological and functional properties of the DG in the epileptic brain, the roles of mossy fiber sprouting and neurogenesis in the development of TE, and impairments to the cognitive functions of the hippocampus when the dentate gyrus loses its protective role in conditions of hyperactivation.
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Adams, B., Lee, M., Fahnestock, M., and Racine, R., “Long-term potentiation trains induce mossy fiber sprouting,” Brain Res., 775, 193–7 (1997).
Avanzi, R. D., Cavarsan, C. F., and Santos, J. G., Jr., et al., “Basal dendrites are present in newly born dentate granule cells of young but not aged pilocarpine-treated chronic epileptic rats,” Neuroscience, 170, 687–91 (2010).
Axmacher, N., Elger, C. E., and Fell, J., “Ripples in the medial temporal lobe are relevant for human memory consolidation,” Brain, 131, 1806–17 (2008).
Babb, T. L. and Brown, W. J., “Pathological findings in epilepsy,” in: Surgical Treatment of the Epilepsies, Engel, J., Jr. (ed.), Raven Press, New York (1987), pp. 511–540.
Babb, T. L., Kupfer, W. R., Pretorius, J. K., et al., “Synaptic reorganization by mossy fibers in human epileptic fascia dentata,” Neuroscience, 42, 351–363 (1991).
Beck, H., Blümcke, I., Kral, T., et al., “Properties of a delayed rectifier potassium current in dentate granule cells isolated from the hippocampus of patients with chronic temporal lobe epilepsy,” Epilepsia, 37, 892–901 (1996).
Bekirov, I. H., Nagy, V., Svoronos, A., et al., “Cadherin-8 and N-cadherin differentially regulate pre- and postsynaptic development of the hippocampal mossy fiber pathway,” Hippocampus, 18, 349–63 (2008).
Bengzon, J., Kokaia, Z., Elmer, E., et al., “Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures,” Proc. Natl. Acad. Sci. USA, 94, 10,432–10,437 (1997).
Bielefeld, P., van Vliet, E. A., Gorter, J. A., et al., “Different subsets of newborn granule cells: a possible role in epileptogenesis?” Eur. J. Neurosci., 39, No. 1, 1–11 (2014).
Binder, D. K., Croll, S. D., Gall, C. M., and Scharfman, H. E., “BDNF and epilepsy: too much of a good thing?” Trends Neurosci., 24, 47–53 (2001).
Bittencourt, S.. and Covolan, L. C. H., Hamani, C., et al., “Replacement of asymmetric synaptic profi les in the molecular layer of dentate gyrus following cycloheximide in the pilocarpine model in rats,” Front. Psychiatry, 6, 157 (2015).
Blümcke, I., Zuschratter, W., Schewe, J. C., et al., “Cellular pathology of hilar neurons in Ammon’s horn sclerosis,” J. Comp. Neurol., 414, 437–453 (1999).
Bragin, A., Benassi, S. K., Kheiri, F., and Engel, J., Jr., “Further evidence that pathological high frequency oscillations are bursts of population spikes derived from recordings of identified cells in dentate gyrus,” Epilepsia, 52, No. 1, 45–52 (2011).
Bragin, A., Engel, J. Jr., Wilson, C. L., et al., “High-frequency oscillations in human brain,” Hippocampus, 9, 137–142 (1999a).
Bragin, A., Engel, J. Jr., Wilson, C. L., et al., “Hippocampal and entorhinal cortex high-frequency oscillations (100–500 Hz) in human epileptic brain and in kainic acid-treated rats with chronic seizures,” Epilepsia, 40, 127–137 (1999b).
Bragin, A., Jandó, G., Nádasdy, Z., et al., “Dentate EEG spikes and associated interneuronal population bursts in the hippocampal hilar region of the rat,” J. Neurophysiol., 73, 1691–1705 (1995).
Buckmaster, P. S. and Dudek, F. E., “Network properties of the dentate gyrus in epileptic rats with hilar neuron loss and granule cell axon reorganization,” J. Neurophysiol., 77, 2685–2696 (1997).
Buckmaster, P. S. and Jongen-Rêlo, A. L., “Highly specific neuron loss preserves lateral inhibitory circuits in the dentate gyrus of kainate-induced epileptic rats,” J. Neurosci., 19, No. 21, 9519–9529 (1999).
Buckmaster, P. S. and Lew, F. H., “Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy,” J. Neurosci., 31, 2337–2347 (2011).
Buckmaster, P. S. and Schwartzkroin, P. A., “Hippocampal mossy cell function: a speculative view,” Hippocampus, 4, 393–402 (1994).
Buckmaster, P. S., “Mossy cell dendritic structure quantified and compared with other hippocampal neurons labeled in rats in vivo,” Epilepsia, 53, Suppl. 1, 9–17 (2012).
Buckmaster, P. S., Abrams, E., and Wen, X., “Seizure frequency correlates with loss of dentate gyrus GABAergic neurons in a mouse model of temporal lobe epilepsy,” J. Comp. Neurol., 525, No. 11, 2592–2610 (2017).
Buckmaster, P. S., Strowbridge, B. W., Kunkel, D. D., et al., “Mossy cell axonal projections to the dentate gyrus molecular layer in the rat hippocampal slice,” Hippocampus, 2, 349–362 (1992).
Buckmaster, P., “Does mossy fiber sprouting give rise to the epileptic state?” Adv. Experim. Med. Biol., 813, 161–168 (2014).
Burgess, N., Maguire, E., and O’Keefe, J., “The human hippocampus and spatial and episodic memory,” Neuron, 35, 625–641 (2002).
Cameron, H. A., Woolley, C. S., McEwen, B. S., and Gould, E., “Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat,” Neuroscience, 56, 337–344 (1993).
Cameron, M. C., Zhan, R., and Nadler, J. V., “Morphologic integration of hilar ectopic granule cells into dentate gyrus circuitry in the pilocarpine model of temporal lobe epilepsy,” J. Comp. Neurol., 519, 2175–2192 (2011).
Cavarsan, C. F., Malheiros, J., Hamani, C., et al., “Is mossy fiber sprouting a potential therapeutic target for epilepsy?” Front. Neurol., 9, 1023 (2018).
Cavazos, J. E., Golarai, G., and Sutula, T. P., “Mossy fiber synaptic reorganization induced by kindling: time course of development, progression, and permanence,” J. Neurosci., 11, No. 9, 2795–2803 (1991).
Cho, K.-O., Lybrand, Z. R., Ito, N., et al., “Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline,” Nat. Commun., 6, 6606 (2015).
Colling, S., Khana, M., Collinge, J., and Jefferys, J., “Mossy fibre reorganization in the hippocampus of prion protein null mice,” Brain Res., 755, 28–35 (1997).
Cossart, R., Dinocourt, C., Hirsch, J. C., et al., “Dendritic but not somatic GABAergic inhibition is decreased in experimental epilepsy,” Nat. Neurosci., 4, 52–62 (2001).
Coulter, D. A. and Carlson, G. C., “Functional regulation of the dentate gyrus by GABA-mediated inhibition,” Prog. Brain Res., 163, 235– 243 (2007).
Covolan, L., Ribeiro, L. T., Longo, B. M., and Mello, L. E., “Cell damage and neurogenesis in the dentate granule cell layer of adult rats after pilocarpine- or kainate-induced status epilepticus,” Hippocampus, 10, No. 2, 169–180 (2000).
Cronin, J., Obenaus, A., Houser, C. R., and Dudek, F. E., “Electrophysiology of dentate granule cells after kainate-induced synaptic reorganization of the mossy fibers,” Brain Res., 573, No. 2, 305–310 (1992).
Das, A., Wallace, G. C., Holmes, C., et al., “Hippocampal tissue of patients with refractory temporal lobe epilepsy is associated with astrocyte activation, inflammation, and altered expression of channels and receptors,” Neuroscience, 220, 237–246 (2012).
Dashtipour, K., Tran, P. H., Okazaki, M. M., et al., “Ultrastructural features and synaptic connections of hilar ectopic granule cells in the rat dentate gyrus are different from those of granule cells in the granule cell layer,” Brain Res., 890, 261–271 (2001).
de Lanerolle, N. C., Brines, M. L., Kim, J. H., et al., “Neurochemical remodeling of the hippocampus in human temporal lobe epilepsy,” in: Epilepsy Research Supplement, Engel, J. Jr. (ed.), Elsevier Science, Amsterdam (1992), Vol. 1, No. 9, pp. 205–220.
Dengler, C. G. and Coulter, D. A., “Normal and epilepsy-associated pathologic function of the dentate gyrus,” Prog. Brain Res., 226, 155–78 (2016).
Dudek, F., “Seizure-induced neurogenesis and epilepsy: involvement of ectopic granule cells?” Epilepsy Curr., 4, 103–104 (2004).
El Bahh, B., Lespinet, V., Lurton, D., et al., “Correlations between granule cell dispersion, mossy fiber sprouting, and hippocampal cell loss in temporal lobe epilepsy,” Epilepsia, 40, 1393–1401 (1999).
Elmer, E., Kokaia, Z., Kokaia, M., et al., “Mossy fibre sprouting: evidence against a facilitatory role in epileptogenesis,” Neuroreport, 8, 1193–1196 (1997).
Engel, J. Jr., “A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology,” Epilepsia, 42, 796–803 (2001).
Frauscher, B., von Ellenrieder, N., Ferrari-Marinho, T., et al., “Facilitation of epileptic activity during sleep is mediated by high amplitude slow waves,” Brain, 138, 1629–1641 (2015).
Freund, T. F. and Buzsaki, G., “Interneurons of the hippocampus,” Hippocampus, 4, 347–470 (1996).
Gabriel, S., Njunting, M., Pomper, J. K., et al., “Stimulus and potassium-induced epileptiform activity in the human dentate gyrus from patients with and without hippocampal sclerosis,” J. Neurosci., 24, 10416–10430 (2004).
Gilbert, P. E., Kesner, R. P., and Lee, I., “Dissociating hippocampal subregions: double dissociation between dentate gyrus and CA1,” Hippocampus, 11, 626–636 (2001).
Gorter, J., van Vliet, E., Aronica, E., and Lopes da Silva, F., “Progression of spontaneous seizures after status epilepticus is associated with mossy fibre sprouting and extensive bilateral loss of hilar parvalbumin and somatostatin-immunoreactive neurons,” Eur. J. Neurosci. Biobehav. Rev., 13, 657–669 (2001).
Haglid, K. G., Wang, S., Qiner, Y., and Hamberger, A., “Excitotoxicity. Experimental correlates to human epilepsy,” Mol. Neurobiol., 9, 259–263 (1994).
Harvey, B. D. and Sloviter, R. S., “Hippocampal granule cell activity and c-Fos expression during spontaneous seizures in awake, chronically epileptic, pilocarpine-treated rats: implications for hippocampal epileptogenesis,” J. Comp. Neurol., 488, 442–463 (2005).
Heinemann, U., Beck, H., Dreier, J. P., et al., “The dentate gyrus as a regulated gate for the propagation of epileptiform activity,” Epilepsy Res. Suppl., 7, 273–280 (1992).
Hendricks, L., Chen, Y., Bensen, A., et al., “Short-term depression of sprouted mossy fiber synapses from adult-born granule cells,” J. Neurosci., 37, 5722–5735 (2017).
Heng, K., Haney, M., and Buckmaster, P., “High-dose rapamycin blocks mossy fiber sprouting but not seizures in a mouse model of temporal lobe epilepsy,” Epilepsia, 54, 1535–1541 (2013).
Hester, M. S. and Danzer, S. C., “Accumulation of abnormal adult-generated hippocampal granule cells predicts seizure frequency and severity,” J. Neurosci., 33, 8926–8936 (2013).
Holtmaat, A., Gorter, J., De Wit, J., et al., “Transient downregulation of Sema3A mRNA in a rat model for temporal lobe epilepsy. A novel molecular event potentially contributing to mossy fi ber sprouting,” Exp. Neurol., 182, 142–150 (2003).
Hosford, B. E., Liska, J. P., and Danzer, S. C., “Ablation of newly generated hippocampal granule cells has disease-modifying effects in epilepsy,” J. Neurosci., 36, No. 43, 11013–11023 (2016).
Houser, C. R., “Granule cell dispersion in the dentate gyrus of humans with temporal lobe epilepsy,” Brain Res., 535, 195–204 (1990).
Houser, C. R., “Morphological changes in the dentate gyrus in human temporal lobe epilepsy,” Epilepsy Res. Suppl., 7, 223–234 (1992).
Hsu, D., “The dentate gyrus as a fi lter or gate: a look back and a look ahead,” Prog. Brain Res., 163, 601–613 (2007).
Ikegaya, Y., “Abnormal targeting of developing hippocampal mossy fibers after epileptiform activities via L-type Ca2+ channel activation in vitro,” J. Neurosci., 19, 802–812 (1999).
Inostroza, M., Brotons-Mas, J. R., Laurent, F., et al., “Specific impairment of ‘what-where-when’ episodic-like memory in experimental models of temporal lobe epilepsy,” J. Neurosci., 33, 17749–17762 (2013).
Isokawa, M., Levesque, M. F., Babb, T. L., and Engel, J., Jr., “Single mossy fiber axonal systems of human dentate granule cells studied in hippocampal slices from patients with temporal lobe epilepsy,” J. Neurosci., 13, No. 4, 1511–1522 (1993).
Jacobs, J., Banks, S., Zelmann, R., et al., “Spontaneous ripples in the hippocampus correlate with epileptogenicity and not memory function in patients with refractory epilepsy,” Epilepsy Behav., 62, 258–266 (2016).
Jacobs, J., LeVan, P., Chander, R., et al., “Interictal highfrequency oscillations (80–500Hz) are an indicator of seizure onset areas independent of spikes in the human epileptic brain,” Epilepsia, 49, 1893–1907 (2008).
Jakubs, K., Nanobashvili, A., Bonde, S., et al., “Environment matters: synaptic properties of neurons born in the epileptic adult brain develop to reduce excitability,” Neuron, 52, 1047–1059 (2006).
Jessberger, S. and Parent, J. M., “Epilepsy and adult neurogenesis,” Cold Spring Harb. Perspect. Biol., 7, a020677 (2015).
Jessberger, S., Römer, B., Babu, H., and Kempermann, G., “Seizures induce proliferation and dispersion of doublecortin-positive hippocampal progenitor cells,” Exp. Neurol., 196, 342–351 (2005).
Johnson, A. M., Sugo, E., Barreto, D., et al., “The severity of gliosis in hippocampal sclerosis correlates with pre-operative seizure burden and outcome after temporal lobectomy,” Mol. Neurobiol., 53, 5446– 5456 (2016).
Jung, K. H., Chu, K., Kim, M., et al., “Continuous cytosine-b-Darabinofuranoside infusion reduces ectopic granule cells in adult rat hippocampus with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus,” Eur. J. Neurosci., 19, 3219– 3226 (2004).
Jung, K. H., Chu, K., Lee, S. T., et al., “Cyclooxygenase-2 inhibitor, celecoxib, inhibits the altered hippocampal neurogenesis with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus,” Neurobiol. Dis., 23, 237–246 (2006).
Kahn, J. B., Port, R. G., Yue, C., et al., “Circuit-based interventions in the dentate gyrus rescue epilepsy-associated cognitive dysfunction,” Brain, 142, No. 9, 2705–2721 (2019).
Karlov, V. A., “Epilepsy as a clinical and neurophysiological challenge,” Zh. Nevrol. Psikhiat., 100, No. 9, 7–15 (2000).
Kelly, T. and Beck, H., “Functional properties of granule cells with hilar basal dendrites in the epileptic dentate gyrus,” Epilepsia, 58, 160– 171 (2017).
Kheirbek, M. A., Drew, L. J., Burghardt, N. S., et al., “Differential control of learning and anxiety along the dorsoventral axis of the dentate gyrus,” Neuron, 77, 955–968 (2013).
Kienzler, F., Norwood, B. A., and Sloviter, R. S., “Hippocampal injury, atrophy, synaptic reorganization, and epileptogenesis after perforant pathway stimulation-induced status epilepticus in the mouse,” J. Comp. Neurol., 515, No. 2, 181–196 (2009).
Koyama, R., Yamada, M. K., Fujisawa, S., et al., “Brain-derived neurotrophic factor induces hyperexcitable reentrant circuits in the dentate gyrus,” J. Neurosci., 24, 7215–7224 (2004).
Kron, M. M., Zhang, H., and Parent, J. M., “The developmental stage of dentate granule cells dictates their contribution to seizure-induced plasticity,” J. Neurosci., 30, 2051–2059 (2010).
Krook-Magnuson, E., Armstrong, C., Bui, A., et al., “In vivo evaluation of the dentate gate theory in epilepsy,” J. Physiol., 593, No. 10, 2379– 2388 (2015).
Liu, R., Lemieux, L., Bell, G., et al., “Cerebral damage in epilepsy: a population- based longitudinal quantitative MRI study,” Epilepsia, 46, 1482–1494 (2005).
Longo, B., Covolan, L., Chadi, G., and Mello, L., “Sprouting of mossy fibers and the vacating of postsynaptic targets in the inner molecular layer of the dentate gyrus,” Exp. Neurol., 181, 57–67 (2003).
Loscher, W. and Schmidt, D., “New horizons in the development of antiepileptic drugs: the search for new targets,” Epilepsy Res., 60, 77–159 (2004).
Lothman, E. and Bertram, E., “Epileptogenic effects of status epilepticus,” Epilepsia, 34, 59–70 (1993).
Lowenstein, D. H., “Structural reorganization of hippocampal networks caused by seizure activity,” Int. Rev. Neurobiol., 45, 209–236 (2001).
Malheiros, J., Paiva, F., Longo, B., et al., “Manganese-enhanced MRI: biological applications in neuroscience,” Front. Neurol., 6, 161 (2015).
Mathern, G. W., Babb, T. L., and Armstrong, D. L., “Hippocampal sclerosis,” in: Epilepsy: a Comprehensive Textbook, Engel, J., Jr. and Pedley, T. A. (eds.), Lippincott-Raven Publishers, Philadelphia (1997), pp, 133–155.
Mathern, G. W., Pretorius, J. K., Leite, J. P., et al., “Hippocampal AMPA and NMDA mRNA Levels and subunit immunoreactivity in human temporal lobe epilepsy patients and a rodent model of chronic mesial limbic epilepsy,” Epilepsy Res., 32, 154–171 (1998).
Mathern, G., Cifuentes, F., Leite, J., et al., “Hippocampal EEG excitability and chronic spontaneous seizures are associated with aberrant synaptic reorganization in the rat intrahippocampal kainate model,” Electroencephalogr. Clin. Neurophysiol., 87, 326–339 (1993).
McNamara, J., “Cellular and molecular basis of epilepsy,” J. Neurosci., 14, 3413–3425 (1994).
Mello, L. and Covolan, L., “Neuronal injury and progressive cell damage,”in: Encyclopedia of Basic Epilepsy Research, Schwartzkroin, P. A. (ed.), Academic Press, London (2009), pp. 125–128.
Mello, L., Cavalheiro, E., Tan, A., et al., “Granule cell dispersion in relation to mossy fiber sprouting, hippocampal cell loss, silent period and seizure frequency in the pilocarpine model of epilepsy,” Epilepsy Res., 9, 51–59 (1992).
Mitsueda-Ono, T., Ikeda, A., Sawamoto, N., et al., “Internal structural changes in the hippocampus observed on 3-tesla MRI in patients with mesial temporal lobe epilepsy,” Intern. Med., 52, 877–885 (2013).
Morimoto, K., Fahnestock, M., and Racine, R. J., “Kindling and status epilepticus models of epilepsy: rewiring the brain,” Prog. Neurobiol., 73, 1–60 (2004).
Myers, C. E., Bermudez-Hernandez, K., and Scharfman, H. E., “The influence of ectopic migration of granule cells into the hilus on dentate gyrus-CA3 function,” PLoS One, 8, e68208 (2013).
Nadler, J. V., “The recurrent mossy fiber pathway of the epileptic brain,” Neurochem. Res., 28, 1649–1658 (2003).
Nadler, J. V., Perry, B. W., and Cotman, C. W., “Selective reinnervation of hippocampal area CA1 and the fascia dentata after destruction of CA3-CA4 afferents with kainic acid,” Brain Res., 182, 1–9 (1980).
Nairismägi, J., Pitkänen, A., Narkilahti, S., et al., “Manganese-enhanced magnetic resonance imaging of mossy fi ber plasticity in vivo,” Neuro- Image, 30, 130–5 (2006).
Nakashiba, T., Cushman, J. D., Pelkey, K. A., et al., “Young dentate granule cells mediate pattern separation, whereas old granule Cells facilitate pattern completion,” Cell, 149, 188–201 (2012).
Nissinen, J., Lukasiuk, K., and Pitkänen, A., “Is mossy fiber sprouting present at the time of the fi rst spontaneous seizures in rat experimental temporal lobe epilepsy?” Hippocampus, 11, 299–310 (2001).
Obenaus, A., Esclapez, M., and Houser, C. R., “Loss of glutamate decarboxylase mRNA-containing neurons in the rat dentate gyrus following pilocarpine-induced seizures,” J. Neurosci., 13, No. 10, 4470– 4485 (1993).
Olney, J. W., “Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate,” Science, 164, 719–721 (1969).
Parent, J. M., Elliott, R. C., Pleasure, S. J., et al., “Aberrant seizure-induced neurogenesis in experimental temporal lobe epilepsy,” Ann. Neurol., 59, 81–91 (2006).
Parent, J. M., Tada, E., Fike, J. R., and Lowenstein, D. H., “Inhibition of dentate granule cell neurogenesis with brain irradiation does not pre vent seizure-induced mossy fi ber synaptic reorganization in the rat,” J. Neurosci., 19, 4508–4519 (1999).
Parent, J., Yu, T., Leibowitz, R., et al., “Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus,” J. Neurosci., 17, 3727–3738 (1997).
Pekcec, A., Lupke, M., Baumann, R., et al., “Modulation of neurogenesis by targeted hippocampal irradiation fails to affect kindling progression,” Hippocampus, 21, 866–876 (2011).
Pierce, J., Melton, J., Punsoni, M., et al., “Mossy fibers are the primary source of afferent input to ectopic granule cells that are born after pilocarpine-induced seizures,” Exp. Neurol., 196, 316–331 (2005).
Pierce, J., Punsoni, M., McCloskey, D., and Scharfman, H., “Mossy cell axon synaptic contacts on ectopic granule cells that are born following pilocarpine-induced seizures,” Neurosci. Lett., 422, 136–140 (2007).
Polli, R., Malheiros, J., Dos Santos, R., et al., “Changes in hippocampal volume are correlated with cell loss but not with seizure frequency in two chronic models of temporal lobe epilepsy,” Front. Neurol., 5, 111 (2014).
Pun, R. Y., Rolle, I. J., Lasarge, C. L., et al., “Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy,” Neuron, 75, 1022–1034 (2012).
Raedt, R., Boon, P., Persson, A., et al., “Radiation of the rat brain suppresses seizure-induced neurogenesis and transiently enhances excitability during kindling acquisition,” Epilepsia, 48, 1952–1963 (2007).
Ratzliff, A. H., Howard, A. L., Santhakumar, V., et al., “Rapid deletion of mossy cells does not result in a hyperexcitable dentate gyrus: Implications for epileptogenesis,” J. Neurosci., 24, No. 9, 2259– 2269 (2004).
Ratzliff, A. H., Santhakumar, V., Howard, A., and Soltesz, I., “Mossy cells in epilepsy: Rigor mortis or vigor mortis?” Trends Neurosci., 25, 140–144 (2002).
Ren, E. and Curia, G., “Synaptic reshaping and neuronal outcomes in the temporal lobe epilepsy,” Int. J. Mol. Sci., 22, No. 8, 3860 (2021).
Represa, A., Jorquera, I., Le Gal La Salle, G., and Ben-Ari, Y., “Epilepsy induced collateral sprouting of hippocampal mossy fibers: does it induce the development of ectopic synapses with granule cell dendrites?” Hippocampus, 3, No. 3, 257–268 (1993).
Reyes-Garcia, S. Z., Scorza, C. A., Araújo, N. S., et al., “Different patterns of epileptiform-like activity are generated in the sclerotic hippocampus from patients with drug-resistant temporal lobe epilepsy,” Sci. Rep., 8, 7116 (2018).
Ribak, C. E., Shapiro, L. A., Yan, X.-X., et al., “Seizure-induced formation of basal dendrites on granule cells of the rodent dentate gyrus,” Jasper’s Basic Mechanisms of the Epilepsies, Noebels, J. L. et al. (eds.), National Center for Biotechnology Information (US), Bethesda (MD) (2012).
Roth, B. L., “DREADDs for neuroscientists,” Neuron, 89, No. 4, 683–694 (2016).
Sanchez, R., Ribak, C., and Shapiro, L., “Synaptic connections of hilar basal dendrites of dentate granule cells in a neonatal hypoxia model of epilepsy,” Epilepsia, 53, 98–108 (2012).
Santhakumar, V., Bender, R., Frotscher, M., et al., “Granule cell hyperexcitability in the early post-traumatic rat dentate gyrus: the ‘irritable mossy cell’ hypothesis,” J. Physiol., 524, No. 1, 117–134 (2000).
Scharfman, H. E. and Myers, C. E., “Hilar mossy cells of the dentate gyrus: a historical perspective,” Front. Neural Circuits, 6, 106 (2012).
Scharfman, H. E. and Pierce, J. P., “New insights into the role of hilar ectopic granule cells in the dentate gyrus based on quantitative anatomic analysis and three-dimensional reconstruction,” Epilepsia, 53, Suppl. 1, 98–108 (2012).
Scharfman, H. E., “Epilepsy as an example of neural plasticity,” Neuroscientist, 8, 154–173 (2002).
Scharfman, H. E., “The role of nonprincipal cells in dentate gyrus excitability and its relevance to animal models of epilepsy and temporal lobe epilepsy,” Adv. Neurol., 79, 805–820 (1999).
Scharfman, H. E., Goodman, J. H., and Sollas, A. L., “Granule-like neurons at the hilar/CA3 border after status epilepticus and their synchrony with area CA3 pyramidal cells: functional implications of seizure-induced neurogenesis,” J. Neurosci., 20, 6144–6158 (2000).
Scharfman, H. E., Synaptic Plasticity and Transsynaptic Signalling, Stanton, P. K. et al. (eds.) Springer (2005), pp. 201–220.
Scharfman, H., Goodman, J., and McCloskey, D., “Ectopic granule cells of the rat dentate gyrus,” Dev. Neurosci., 29, 14–27 (2007).
Schmeiser, B., Li, J., Brandt, A., Zentner, J., et al., “Different mossy fiber sprouting patterns in ILAE hippocampal sclerosis types,” Epilepsy Res., 136, 115–122 (2017).
Scott, B., Wojtowicz, J., and Burnham, W., “Neurogenesis in the dentate gyrus of the rat following electroconvulsive shock seizures,” Exp. Neurol., 165, 231–236 (2000).
Shapiro, L. A., Figueroa-Aragon, S., and Ribak, C. E., “Newly generated granule cells show rapid neuroplastic changes in the adult rat dentate gyrus during the first five days following pilocarpine-induced seizures,” Eur. J. Neurosci., 26, No. 3, 583–592 (2007).
Shibata, K., Nakahara, S., Shimizu, E., et al., “Repulsive guidance molecule a regulates hippocampal mossy fiber branching in vitro,” Neuroreport, 24, 609–615 (2013).
Sloviter, R. S., “Feedforward and feedback inhibition of hippocampal principal cell activity evoked by perforant path stimulation: GABAmediated mechanisms that regulate excitability in vivo,” Hippocampus, 1, 31–40 (1991a).
Sloviter, R. S., “Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: the “dormant basket cell” hypothesis and its possible relevance to temporal lobe epilepsy,” Hippocampus, 1, 41–66 (1991b).
Sloviter, R. S., “Status epilepticus-induced neuronal injury and network reorganization,” Epilepsia, 40, Suppl. 1, S34–9, Discuss. S40-1 (1999).
Sloviter, R. S., “The functional organization of the hippocampal dentate gyrus and its relevance to the pathogenesis of temporal lobe epilepsy,” Ann. Neurol., 35, 640–654 (1994).
Sloviter, R., “Decreased hippocampal inhibition and selective loss of interneurons in experimental epilepsy,” Science, 235, 73–76 (1987).
Sloviter, R., Bumanglag, A., Schwarcz, R., and Frotscher, M., “Abnormal dentate gyrus network circuitry in temporal lobe epilepsy,” in: Jasper’s Basic Mechanisms of the Epilepsies, Noebels, J. L. et al. (eds.), National Center for Biotechnology Information (US), Bethesda (MD) (2012).
Song, I., Orosz, I., Chervoneva, I., et al., “Bimodal coupling of ripples and slower oscillations during sleep in patients with focal epilepsy,” Epilepsia, 58, 1972–1984 (2017).
Song, M. Y., Tian, F. F., Wang, Y. Z., et al., “Potential roles of the RGMa-FAK-Ras pathway in hippocampal mossy fiber sprouting in the pentylenetetrazole kindling model,” Mol. Med. Rep., 11, 1738–1744 (2015).
Spigelman, I., Yan, X., Obenaus, A., et al., “Dentate granule cells form novel basal dendrites in a rat model of temporal lobe epilepsy,” Neuroscience, 86, 109–120 (1998).
Staba, R. J., Wilson, C. L., Bragin, A., et al., “Quantitative analysis of high-frequency oscillations (80–500 Hz) recorded in human epileptic hippocampus and entorhinal cortex,” J. Neurophysiol., 88, 1743–1752 (2002).
Sun, C., Mtchedlishvili, Z., Bertram, E. H., et al., “Selective loss of dentate hilar interneurons contributes to reduced synaptic inhibition of granule cells in an electrical stimulation-based animal model of temporal lobe epilepsy,” J. Comp. Neurol., 500, 876–893 (2007).
Sutula, T. P. and Dudek, F. E., “Unmasking recurrent excitation generated by mossy fiber sprouting in the epileptic dentate gyrus: an emergent property of a complex system,” Prog. Brain Res., 163, 541–563 (2007).
Sutula, T., Cascino, G., Cavazos, J., et al., “Mossy fiber synaptic reorganization in the epileptic human temporal lobe,” Ann. Neurol., 26, 321–330 (1989).
Tamagnone, L. and Comoglio, P., “Signalling by semaphorin receptors: cell guidance and beyond,” Trends Cell Biol., 10, 377–383 (2000).
Tauck D and Nadler, J., “Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats,” J. Neurosci., (1985) 5: 1016– 22.
Thind, K. K., Ribak, C. E., and Buckmaster, P. S., “Synaptic input to dentate granule cell basal dendrites in a rat model of temporal lobe epilepsy,” J. Comp. Neurol., 509, 190–202 (2008).
Tong, X., Tong, X., Peng, Z., et al., “Ectopic expression of α6 and δ GABAA receptor subunits in hilar somatostatin neurons increases tonic inhibition and alters network activity in the dentate gyrus,” J. Neurosci., 35, 16142–16158 (2015).
Tulving, E., “Episodic memory: from mind to brain,” Annu. Rev. Psychol., 53, 1–25 (2002).
Ueda, Y., Doi, T., Tsuru, N., et al., “Expression of glutamate transporters and ionotropic glutamate receptors in GLAST knockout mice,” Brain Res. Mol. Brain Res., 104, No. 2, 120–126 (2002).
Van Paesschen, W., Revesz, T., Duncan, J. S., et al., “Quantitative neuropathology and quantitative magnetic resonance imaging of the hippocampus in temporal lobe epilepsy,” Ann. Neurol., 42, 756–766 (1997).
Viscomi, M. T., Oddi, S., Latini, L., et al., “The endocannabinoid system: A new entry in remote cell death mechanisms,” Exp. Neurol., 224, 56–65 (2010).
von Ellenrieder, N., Frauscher, B., Dubeau, F., and Gotman, J., “Interaction with slow waves during sleep improves discrimination of physiologic and pathologic high-frequency oscillations (80–500Hz),” Epilepsia, 57, 869–878 (2016).
Walter, C., Murphy, B. L., Pun, R. Y., et al., “Pilocarpine-induced seizures cause selective time-dependent changes to adult-generated hippocampal dentate granule cells,” J. Neurosci., 27, 7541–7552 (2007).
Weiss, S. A., Song, I., Leng, M., et al., “Ripples have distinct spectral properties and phase-amplitude coupling with slow waves, but indistinct unit firing, in human epileptogenic hippocampus,” Front. Neurol., 11, 174 (2020).
Wittner, L., Maglóczky, Z., Borhegyi, Z., et al., “Preservation of perisomatic inhibitory input of granule cells in the epileptic human dentate gyrus,” Neuroscience, 108, 587–600 (2001).
Wuarin, J. P. and Dudek, F. E., “Excitatory synaptic input to granule cells increases with time after kainate treatment,” J. Neurophysiol., 85, No. 3, 1067–1077 (2001).
Yamawaki, R., Thind, K., and Buckmaster, P. S., “Blockade of excitatory synaptogenesis with proximal dendrites of dentate granule cells following rapamycin treatment in a mouse model of temporal lobe epilepsy,” J. Comp. Neurol., 523, 281–297 (2015).
Zeng, L. H., Rensing, N. R., and Wong, M., “The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy,” J. Neurosci., 29, 6964–6972 (2009).
Zhan, R. Z., Timofeeva, O., and Nadler, J. V., “High ratio of synaptic excitation to synaptic inhibition in hilar ectopic granule cells of pilocarpine- treated rats,” J. Neurophysiol., 104, 3293–3304 (2010).
Zhang, Y., Xiong, T., Tan, B., et al., “Pilocarpine-induced epilepsy is associated with actin cytoskeleton reorganization in the mossy fiber-CA3 synapses,” Epilepsy Res., 108, 379–389 (2014).
Zimmer, J., “Changes in the Timm sulfide silver staining patter of the rat hippocampus and fascia dentata following early postnatal deafferentiation,” Brain Res., 64, 313–326 (1973).
Zimmer, J., “Long-term synaptic reorganization in rat fascia dentate deafferented at adolescent and adult stages: observations with the Timm method,” Brain Res., 76, 336–342 (1974).
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Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 72, No. 3, pp. 343–359, May–June, 2022.
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Kitchigina, V.F., Shubina, L.V. & Popova, I.Y. The Role of the Dentate Gyrus in Mediating Hippocampal Functions: The Epileptic Brain. Neurosci Behav Physi 52, 1418–1428 (2022). https://doi.org/10.1007/s11055-023-01373-0
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DOI: https://doi.org/10.1007/s11055-023-01373-0