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Cited by 12Epilepsy research and treatmentNeuroscience and Neuropharmacology ResearchMemory and Neural Mechanisms

Differential vulnerability of neuronal subpopulations of the subiculum in a mouse model for mesial temporal lobe epilepsy

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Franz, Julia, Barheier, Nicole, Wilms, Henrike, Tulke, Susanne, Haas, Carola A., Häussler, Ute·2023·Frontiers in Cellular Neuroscience
DOI 10.3389/fncel.2023.1142507PMC PMC10090355
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Abstract

Selective loss of inhibitory interneurons (INs) that promotes a shift toward an excitatory predominance may have a critical impact on the generation of epileptic activity. While research on mesial temporal lobe epilepsy (MTLE) has mostly focused on hippocampal changes, including IN loss, the subiculum as the major output region of the hippocampal formation has received less attention. The subiculum has been shown to occupy a key position in the epileptic network, but data on cellular alterations are controversial. Using the intrahippocampal kainate (KA) mouse model for MTLE, which recapitulates main features of human MTLE such as unilateral hippocampal sclerosis and granule cell dispersion, we identified cell loss in the subiculum and quantified changes in specific IN subpopulations along its dorso-ventral axis. We performed intrahippocampal recordings, FluoroJade C-staining for degenerating neurons shortly after status epilepticus (SE), fluorescence in situ hybridization for glutamic acid decarboxylase (Gad) 67 mRNA and immunohistochemistry for neuronal nuclei (NeuN), parvalbumin (PV), calretinin (CR) and neuropeptide Y (NPY) at 21 days after KA. We observed remarkable cell loss in the ipsilateral subiculum shortly after SE, reflected in lowered density of NeuN+ cells in the chronic stage when epileptic activity occurred in the subiculum concomitantly with the hippocampus. In addition, we show a position-dependent reduction of Gad67-expressing INs by ∼50% (along the dorso-ventral as well as transverse axis of the subiculum). This particularly affected the PV- and to a lesser extent CR-expressing INs. The density of NPY-positive neurons was increased, but the double-labeling for Gad67 mRNA expression revealed that an upregulation or de novo expression of NPY in non-GABAergic cells with a concomitant reduction of NPY-positive INs underlies this observation. Our data suggest a position- and cell type-specific vulnerability of subicular INs in MTLE, which might contribute to hyperexcitability of the subiculum, reflected in epileptic activity.

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Research works printed but not linked: 48

  1. Arellano J. I. Muñoz A. Ballesteros-Yáñez I. Sola R. G. DeFelipe J. (2004). Histopathology and reorganization of chandelier cells in the human epileptic sclerotic hippocampus. Brain 127 45– 64. 10.1093/brain/awh004 14534159 · DOI
  2. Behr J. Heinemann U. (1996). Low Mg2+ induced epileptiform activity in the subiculum before and after disconnection from rat hippocampal and entorhinal cortex slices. Neurosci. Lett. 205 25– 28. 10.1016/0304-3940(96)12360-0 8867012 · DOI
  3. Blümcke I. Beck H. Nitsch R. Eickhoff C. Scheffler B. Celio M. R. (1996). Preservation of calretinin-immunoreactive neurons in the hippocampus of epilepsy patients with Ammon’s horn sclerosis. J. Neuropathol. Exp. Neurol. 55 329– 341. 8786391
  4. Blümcke I. Thom M. Aronica E. Armstrong D. D. Bartolomei F. Bernasconi A. (2013). International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: a task force report from the ILAE commission on Diagnostic methods. Epilepsia 54 1315– 1329. 23692496
  5. Böhm C. Peng Y. Maier N. Winterer J. Poulet J. F. A. Geiger J. R. P. (2015). Functional diversity of subicular principal cells during hippocampal ripples. J. Neurosci. 35 13608– 13618. 10.1523/JNEUROSCI.5034-14.2015 26446215 PMC4595619 · DOI
  6. Cembrowski M. S. Phillips M. G. DiLisio S. F. Shields B. C. Winnubst J. Chandrashekar J. (2018a). Dissociable structural and functional hippocampal outputs via distinct subiculum cell classes. Cell 173 1280– 1292.e18. 29681453
  7. Cohen I. Navarro V. Clemenceau S. Baulac M. Miles R. (2002). On the origin of interictal activity in human temporal lobe epilepsy in vitro. Science 298 1418– 1421. 12434059
  8. Depaulis A. Hamelin S. (2015). Animal models for mesiotemporal lobe epilepsy: the end of a misunderstanding? Rev. Neurol. 171 217– 226. 10.1016/j.neurol.2015.01.558 25748330 · DOI
  9. Drexel M. Kirchmair E. Wieselthaler-Hölzl A. Preidt A. P. Sperk G. (2012a). Somatostatin and neuropeptide Y neurons undergo different plasticity in parahippocampal regions in kainic acid-induced epilepsy. J. Neuropathol. Exp. Neurol. 71 312– 329. 10.1097/NEN.0b013e31824d9882 22437342 PMC3399768 · DOI
  10. Drexel M. Preidt A. P. Sperk G. (2012b). Sequel of spontaneous seizures after kainic acid-induced status epilepticus and associated neuropathological changes in the subiculum and entorhinal cortex. Neuropharmacology 63 806– 817. 10.1016/j.neuropharm.2012.06.009 22722023 PMC3409872 · DOI
  11. Drexel M. Preidt A. P. Kirchmair E. Sperk G. (2011). Parvalbumin interneurons and calretinin fibers arising from the thalamic nucleus reuniens degenerate in the subiculum after kainic acid-induced seizures. Neuroscience 189 316– 329. 10.1016/j.neuroscience.2011.05.021 21616128 PMC3152681 · DOI
  12. Fabó D. Maglóczky Z. Wittner L. Pék A. Eross L. Czirják S. (2008). Properties of in vivo interictal spike generation in the human subiculum. Brain 131 485– 499. 10.1093/brain/awm297 18083752 · DOI
  13. Fiske M. P. Anstötz M. Welty L. J. Maccaferri G. (2020). The intrinsic cell type-specific excitatory connectivity of the developing mouse subiculum is sufficient to generate synchronous epileptiform activity. J. Physiol. 598 1965– 1985. 10.1113/JP279561 32119127 PMC7382390 · DOI
  14. Franklin K. B. J. Paxinos G. (2008). The Mouse Brain in Stereotaxic Coordinates, 3rd Edn. San Diego: Academic Press.
  15. Froriep U. P. Kumar A. Cosandier-Rimélé D. Häussler U. Kilias A. Haas C. A. (2012). Altered θ coupling between medial entorhinal cortex and dentate gyrus in temporal lobe epilepsy. Epilepsia 53 1937– 1947. 10.1111/j.1528-1167.2012.03662.x 22984867 · DOI
  16. Fujise N. Hunziker W. Heizmann C. W. Kosaka T. (1995). Distribution of the calcium binding proteins, calbindin D-28K and parvalbumin, in the subicular complex of the adult mouse. Neurosci. Res. 22 89– 107. 10.1016/0168-0102(95)00882-t 7792085 · DOI
  17. Greene J. R. Totterdell S. (1997). Morphology and distribution of electrophysiologically defined classes of pyramidal and nonpyramidal neurons in rat ventral subiculum in vitro. J. Comp. Neurol. 380 395– 408. 10.1002/(sici)1096-9861(19970414)380:3<395::aid-cne8>3.0.co;2-y 9087521 · DOI
  18. Haas C. A. Dudeck O. Kirsch M. Huszka C. Kann G. Pollak S. (2002). Role for reelin in the development of granule cell dispersion in temporal lobe epilepsy. J. Neurosci. 22 5797– 5802. 12122039 PMC6757930
  19. Häussler U. Bielefeld L. Froriep U. P. Wolfart J. Haas C. A. (2012). Septotemporal position in the hippocampal formation determines epileptic and neurogenic activity in temporal lobe epilepsy. Cereb. Cortex 22 26– 36. 10.1093/cercor/bhr054 21572089 · DOI
  20. Häussler U. Rinas K. Kilias A. Egert U. Haas C. A. (2016). Mossy fiber sprouting and pyramidal cell dispersion in the hippocampal CA2 region in a mouse model of temporal lobe epilepsy. Hippocampus 26 577– 588. 10.1002/hipo.22543 26482541 · DOI
  21. He D. F. Ma D. L. Tang Y. C. Engel J. Bragin A. Tang F. R. (2010). Morpho-physiologic characteristics of dorsal subicular network in mice after pilocarpine-induced status epilepticus. Brain Pathol. 20 80– 95. 10.1111/j.1750-3639.2009.00243.x 19298597 PMC3000123 · DOI
  22. Heinrich C. Nitta N. Flubacher A. Müller M. Fahrner A. Kirsch M. (2006). Reelin deficiency and displacement of mature neurons, but not neurogenesis, underlie the formation of granule cell dispersion in the epileptic hippocampus. J. Neurosci. 26 4701– 4713. 10.1523/JNEUROSCI.5516-05.2006 16641251 PMC6674063 · DOI
  23. Houser C. R. (1990). Granule cell dispersion in the dentate gyrus of humans with temporal lobe epilepsy. Brain Res. 535 195– 204. 1705855
  24. Ishihara Y. Fukuda T. (2016). Immunohistochemical investigation of the internal structure of the mouse subiculum. Neuroscience 337 242– 266. 27664459
  25. Janz P. Savanthrapadian S. Häussler U. Kilias A. Nestel S. Kretz O. (2017a). Synaptic remodeling of entorhinal input contributes to an aberrant hippocampal network in temporal lobe epilepsy. Cereb. Cortex 27 2348– 2364. 10.1093/cercor/bhw093 27073230 · DOI
  26. Janz P. Schwaderlapp N. Heining K. Häussler U. Korvink J. G. von Elverfeldt D. (2017b). Early tissue damage and microstructural reorganization predict disease severity in experimental epilepsy. elife 6: e25742. 10.7554/eLife.25742 28746029 PMC5529108 · DOI
  27. Kilias A. Häussler U. Heining K. Froriep U. P. Haas C. A. Egert U. (2018). Theta frequency decreases throughout the hippocampal formation in a focal epilepsy model. Hippocampus 28 375– 391. 10.1002/hipo.22838 29473981 · DOI
  28. Kilias A. Tulke S. Barheier N. Ruther P. Häussler U. (2023). Integration of the CA2 region in the hippocampal network during epileptogenesis. Hippocampus 33 223– 240. 10.1002/hipo.23479 36421040 · DOI
  29. Klapstein G. J. Colmers W. F. (1997). Neuropeptide Y suppresses epileptiform activity in rat hippocampus in vitro. J. Neurophysiol. 78 1651– 1661. 10.1152/jn.1997.78.3.1651 9310450 · DOI
  30. Knopp A. Frahm C. Fidzinski P. Witte O. W. Behr J. (2008). Loss of GABAergic neurons in the subiculum and its functional implications in temporal lobe epilepsy. Brain 131 1516– 1527. 10.1093/brain/awn095 18504292 · DOI
  31. Knopp A. Kivi A. Wozny C. Heinemann U. Behr J. (2005). Cellular and network properties of the subiculum in the pilocarpine model of temporal lobe epilepsy. J. Comp. Neurol. 483 476– 488. 10.1002/cne.20460 15700275 · DOI
  32. Kulik A. Vida I. Luján R. Haas C. A. López-Bendito G. Shigemoto R. (2003). Subcellular localization of metabotropic GABA(B) receptor subunits GABA(B1a/b) and GABA(B2) in the rat hippocampus. J. Neurosci. 23 11026– 11035. 10.1523/JNEUROSCI.23-35-11026.2003 14657159 PMC6741037 · DOI
  33. Ledri M. Sørensen A. T. Madsen M. G. Christiansen S. H. Ledri L. N. Cifra A. (2015). Differential effect of neuropeptides on excitatory synaptic transmission in human epileptic hippocampus. J. Neurosci. 35 9622– 9631. 26134645 PMC6605141
  34. Lisgaras C. P. Scharfman H. E. (2022). Robust chronic convulsive seizures, high frequency oscillations, and human seizure onset patterns in an intrahippocampal kainic acid model in mice. Neurobiol. Dis. 166: 105637. 10.1016/j.nbd.2022.105637 35091040 PMC9034729 · DOI
  35. Maglóczky Z. Wittner L. Borhegyi Z. Halász P. Vajda J. Czirják S. (2000). Changes in the distribution and connectivity of interneurons in the epileptic human dentate gyrus. Neuroscience 96 7– 25. 10.1016/s0306-4522(99)00474-1 10683405 · DOI
  36. Marx M. Haas C. A. Häussler U. (2013). Differential vulnerability of interneurons in the epileptic hippocampus. Front. Cell Neurosci. 7: 167. 10.3389/fncel.2013.00167 24098270 PMC3787650 · DOI
  37. Paschen E. Elgueta C. Heining K. Vieira D. M. Kleis P. Orcinha C. (2020). Hippocampal low-frequency stimulation prevents seizure generation in a mouse model of mesial temporal lobe epilepsy. Elife 9: e54518. 10.7554/eLife.54518 33349333 PMC7800381 · DOI
  38. Patrylo P. R. van den Pol A. N. Spencer D. D. Williamson A. (1999). NPY inhibits glutamatergic excitation in the epileptic human dentate gyrus. J. Neurophysiol. 82 478– 483. 10.1152/jn.1999.82.1.478 10400974 · DOI
  39. Sloviter R. S. (1994). On the relationship between neuropathology and pathophysiology in the epileptic hippocampus of humans and experimental animals. Hippocampus 4 250– 253. 7842045
  40. Steward O. (1976). Topographic organization of the projections from the entorhinal area to the hippocampal formation of the rat. J. Comp. Neurol. 167 285– 314. 10.1002/cne.901670303 1270625 · DOI
  41. Sutula T. Cascino G. Cavazos J. Parada I. Ramirez L. (1989). Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann. Neurol. 26 321– 330. 2508534
  42. Suzuki F. Junier M. P. Guilhem D. Sørensen J. C. Onteniente B. (1995). Morphogenetic effect of kainate on adult hippocampal neurons associated with a prolonged expression of brain-derived neurotrophic factor. Neuroscience 64 665– 674. 10.1016/0306-4522(94)00463-f 7715779 · DOI
  43. Taube J. S. (1993). Electrophysiological properties of neurons in the rat subiculum in vitro. Exp. Brain Res. 96 304– 318. 7903643
  44. Thom M. Sisodiya S. M. Beckett A. Martinian L. Lin W.-R. Harkness W. (2002). Cytoarchitectural abnormalities in hippocampal sclerosis. J. Neuropathol. Exp. Neurol. 61 510– 519. 12071634
  45. Tóth E. Bokodi V. Somogyvári Z. Maglóczky Z. Wittner L. Ulbert I. (2021). Laminar distribution of electrically evoked hippocampal short latency ripple activity highlights the importance of the subiculum in vivo in human epilepsy, an intraoperative study. Epilepsy Res. 169: 106509. 10.1016/j.eplepsyres.2020.106509 33310654 PMC7855751 · DOI
  46. Tulke S. Haas C. A. Häussler U. (2019). Expression of brain-derived neurotrophic factor and structural plasticity in the dentate gyrus and CA2 region correlate with epileptiform activity. Epilepsia 60 1234– 1247. 10.1111/epi.15540 31121074 · DOI
  47. Woldbye D. P. Madsen T. M. Larsen P. J. Mikkelsen J. D. Bolwig T. G. (1996). Neuropeptide Y inhibits hippocampal seizures and wet dog shakes. Brain Res. 737 162– 168. 8930362
  48. Wozny C. Knopp A. Lehmann T.-N. Heinemann U. Behr J. (2005). The subiculum: a potential site of ictogenesis in human temporal lobe epilepsy. Epilepsia 46(Suppl. 5) 17– 21. 15987248

Cited by

Sorted by citations

Authors
Franz, J., Barheier, N., Wilms, H., Tulke, S., Haas, C. A., & Häussler, U.
Affiliations
University of Freiburg (DE)
Corresponding author
Häussler, Ute
ORCID
Venue
Frontiers in Cellular Neuroscience
Publisher
Frontiers Media SA
Published
2023-03-29
Volume
17
Pages
1142507-1142507
ISSN
1662-5102 (ISSN-L)
DOI
10.3389/fncel.2023.1142507
PMC
PMC10090355
OpenAlex
W4361202524
Cited by
12
References
3
Citations by year
2026: 2 · 2025: 5 · 2024: 4 · 2022: 1
FWCI
2.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Deutsche Forschungsgemeinschaft
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
mesial temporal lobe epilepsy, subiculum, inhibitory interneurons, kainate-induced epilepsy, status epilepticus, neuronal vulnerability, parvalbumin interneurons, calretinin interneurons, neuropeptide Y, glutamic acid decarboxylase 67, neuronal loss, hippocampal sclerosis, dorsal-ventral axis

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