The hippocampus is the most common seizure focus in people. In the hippocampus, aberrant neurogenesis plays a critical role in the initiation and progression of epilepsy in rodent models, but it is unknown whether this also holds true in humans. To address this question, we used immunofluorescence on control healthy hippocampus and surgical resections from mesial temporal lobe epilepsy (MTLE), plus neural stem-cell cultures and multi-electrode recordings of ex vivo hippocampal slices. We found that a longer duration of epilepsy is associated with a sharp decline in neuronal production and persistent numbers in astrogenesis. Further, immature neurons in MTLE are mostly inactive, and are not observed in cases with local epileptiform-like activity. However, immature astroglia are present in every MTLE case and their location and activity are dependent on epileptiform-like activity. Immature astroglia, rather than newborn neurons, therefore represent a potential target to continually modulate adult human neuronal hyperactivity.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Transcranial focused ultrasound-mediated unbinding of phenytoin from plasma proteins for suppression of chronic temporal lobe epilepsy in a rodent model
Scientific Reports Open Access 13 March 2023
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 per month
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
All data are available in the manuscript or supplementary materials. Individual data points for each figure are available upon reasonable request from the corresponding author. Any further information regarding the availability of raw data, materials and methods can be directed to the corresponding author.
Bond, A. M., Ming, G. L. & Song, H. Adult mammalian neural stem cells and neurogenesis: five decades later. Cell Stem Cell 17, 385–395 (2015).
Miller, S. M. & Sahay, A. Functions of adult-born neurons in hippocampal memory interference and indexing. Nat. Neurosci. 22, 1565–1575 (2019).
Cho, K.-O. et al. Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat. Commun. 6, 6606 (2015).
Parent, J. M. 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).
Pun, R. Y. K. et al. Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy. Neuron 75, 1022–1034 (2012).
Hattiangady, B., Rao, M. S. & Shetty, A. K. Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus. Neurobiol. Dis. 17, 473–490 (2004).
Kralic, J. E., Ledergerber, D. A. & Fritschy, J.-M. Disruption of the neurogenic potential of the dentate gyrus in a mouse model of temporal lobe epilepsy with focal seizures. Eur. J. Neurosci. 22, 1916–1927 (2005).
Hattiangady, B. & Shetty, A. K. Implications of decreased hippocampal neurogenesis in chronic temporal lobe epilepsy. Epilepsia 49, 26–41 (2008).
Marín-Burgin, A., Mongiat, L. A., Pardi, M. B. & Schinder, A. F. Unique processing during a period of high excitation/inhibition balance in adult-born neurons. Science 335, 1238–1242 (2012).
Zhou, Q. G. et al. Chemogenetic silencing of hippocampal neurons suppresses epileptic neural circuits. J. Clin. Invest. 129, 310–323 (2019).
Varma, P., Brulet, R., Zhang, L. & Hsieh, J. Targeting seizure-induced neurogenesis in a clinically-relevant time-period leads to transient but not persistent seizure reduction. J. Neurosci. 39, 7019–7028 (2019).
Lybrand, Z. R. et al. A critical period of neuronal activity results in aberrant neurogenesis rewiring hippocampal circuitry in a mouse model of epilepsy. Nat. Commun. 12, 1423 (2021).
Sierra, A. et al. Neuronal hyperactivity accelerates depletion of neural stem cells and impairs hippocampal neurogenesis. Cell Stem Cell 16, 488–503 (2015).
Boldrini, M. et al. Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell 22, 589–599.e5 (2018).
Sorrells, S. F. et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555, 377–381 (2018).
Spalding, K. L. et al. Dynamics of hippocampal neurogenesis in adult humans. Cell 153, 1219–1227 (2013).
Eriksson, P. S. et al. Neurogenesis in the adult human hippocampus. Nat. Med. 4, 1313–1317 (1998).
Tobin, M. K. et al. Human hippocampal neurogenesis persists in aged adults and Alzheimer’s disease patients. Cell Stem Cell 24, 974–982.e3 (2019).
Moreno-Jiménez, E. P. et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat. Med. 25, 554–560 (2019).
Cipriani, S. et al. Hippocampal radial glial subtypes and their neurogenic potential in human fetuses and healthy and Alzheimer’s disease adults. Cereb. Cortex 28, 2458–2478 (2018).
Knoth, R. et al. Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years. PLoS One 5, e8809 (2010).
Coras, R. et al. Low proliferation and differentiation capacities of adult hippocampal stem cells correlate with memory dysfunction in humans. Brain 133, 3359–3372 (2010).
Liu, Y. W. J. et al. Doublecortin expression in the normal and epileptic adult human brain. Eur. J. Neurosci. 28, 2254–2265 (2008).
Engel, J. & International League Against Epilepsy (ILAE). 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).
Wiebe, S., Blume, W. T., Girvin, J. P., Eliasziw, M. & Effectiveness and Efficiency of Surgery for Temporal Lobe Epilepsy Study Group. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N. Engl. J. Med. 345, 311–8 (2001).
Zhang, Y. et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89, 37–53 (2016).
Bloch, J. et al. Doublecortin-positive cells in the adult primate cerebral cortex and possible role in brain plasticity and development. J. Comp. Neurol. 519, 775–789 (2011).
Johansson, C. B., Svensson, M., Wallstedt, L., Janson, A. M. & Frisén, J. Neural stem cells in the adult human brain. Exp. Cell Res. 253, 733–736 (1999).
Kukekov, V. G. et al. Multipotent stem/progenitor cells with similar properties arise from two neurogenic regions of adult human brain. Exp. Neurol. 156, 333–44 (1999).
Hsiao, M.-C. et al. An in vitro seizure model from human hippocampal slices using multi-electrode arrays. J. Neurosci. Methods 244, 154–163 (2015).
Pillai, J. & Sperling, M. R. Interictal EEG and the diagnosis of epilepsy. Epilepsia 47, 14–22 (2006).
Gabriel, S. 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).
Simonato, M. et al. Differential expression of immediate early genes in the hippocampus in the kindling model of epilepsy. Brain Res. Mol. Brain Res. 11, 115–24 (1991).
Rakhade, S. N. et al. A common pattern of persistent gene activation in human neocortical epileptic foci. Ann. Neurol. 58, 736–747 (2005).
Adamsky, A. et al. Astrocytic activation generates de novo neuronal potentiation and memory enhancement. Cell 174, 59–71.e14 (2018).
Lam, A. D. et al. Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer’s disease. Nat. Med. 23, 678–680 (2017).
Vossel, K. A. et al. Incidence and impact of subclinical epileptiform activity in Alzheimer’s disease. Ann. Neurol. 80, 858–870 (2016).
Sen, A., Capelli, V. & Husain, M. Cognition and dementia in older patients with epilepsy. Brain 141, 1592–1608 (2018).
Hermann, B., Seidenberg, M., Lee, E. J., Chan, F. & Rutecki, P. Cognitive phenotypes in temporal lobe epilepsy. J. Int. Neuropsychol. Soc. 13, 12–20 (2007).
Segi-Nishida, E., Warner-Schmidt, J. L. & Duman, R. S. Electroconvulsive seizure and VEGF increase the proliferation of neural stem-like cells in rat hippocampus. Proc. Natl Acad. Sci. USA 105, 11352–11357 (2008).
Jang, M. H. et al. Secreted frizzled-related protein 3 regulates activity-dependent adult hippocampal neurogenesis. Cell Stem Cell 12, 215–223 (2013).
Snyder, J. S. Recalibrating the relevance of adult neurogenesis. Trends Neurosci. 42, 164–178 (2019).
Chen, M. et al. Neural progenitor cells in cerebral cortex of epilepsy patients do not originate from astrocytes expressing GLAST. Cereb. Cortex 27, 5672–5682 (2017).
Bonaguidi, M. A. et al. Noggin expands neural stem cells in the adult hippocampus. J. Neurosci. 28, 9194–9204 (2008).
Tian, G.-F. et al. An astrocytic basis of epilepsy. Nat. Med. 11, 973–981 (2005).
Diaz Verdugo, C. et al. Glia-neuron interactions underlie state transitions to generalized seizures. Nat. Commun. 10, 3830 (2019).
Deemyad, T., Lüthi, J. & Spruston, N. Astrocytes integrate and drive action potential firing in inhibitory subnetworks. Nat. Commun. 9, 4336 (2018).
Mu, Y. et al. Glia accumulate evidence that actions are futile and suppress unsuccessful behavior. Cell 178, 27–43.e19 (2019).
de Lanerolle, N. C., Kim, J. H., Robbins, R. J. & Spencer, D. D. Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy. Brain Res. 495, 387–395 (1989).
Schröder, W. et al. Functional and molecular properties of human astrocytes in acute hippocampal slices obtained from patients with temporal lobe epilepsy. Epilepsia 41, S181–S184 (2000).
Nossenson, N., Magal, A. & Messer, H. Detection of stimuli from multi-neuron activity: empirical study and theoretical implications. Neurocomputing 174, 822–837 (2016).
Lewis, D. A. The human brain revisited: opportunities and challenges in postmortem studies of psychiatric disorders. Neuropsychopharmacology 26, 143–154 (2002).
Kelly, T. M. & Mann, J. J. Validity of DSM-III-R diagnosis by psychological autopsy: a comparison with clinician ante-mortem diagnosis. Acta Psychiatr. Scand. 94, 337–343 (1996).
Endicott, J., Spitzer, R. L., Fleiss, J. L. & Cohen, J. The global assessment scale: a procedure for measuring overall severity of psychiatric disturbance. Arch. Gen. Psychiatry 33, 766–771 (1976).
We thank the families that gave consent for brain tissue collection and interviews to investigators at Columbia University, the New York State Psychiatric Institute and the University of Southern California. We thank teams performing the psychological autopsy interviews and M. J. Bakalian for assistance with laboratory equipment and software. We thank the USC Neurorestoration administration and clinical research staff for their support on this study. We thank A. P. McMahon and members of the Bonaguidi laboratory for helpful discussions.
This work was supported by the National Institutes of Health (NIH) (R00NS089013, R56AG064077 to M.A.B.; MH83862, NS090415, MH94888 to M.B.; U01MH098937 to R.H.C.; MH64168, MH098786 to A.J.D.; MH40210 to V.A.; MH090964 to J.J.M.), the Donald E. and Delia B. Baxter Foundation, the L.K. Whittier Foundation, the Eli and Edythe Broad Foundation (to M.A.B.), the USC Neurorestoration Center (to J.J.R. and C.Y.L.), the Rudi Schulte Research Institute (to C.Y.L.), the American Foundation for Suicide Prevention SRG-0-129-12, the Brain and Behavior Research Foundation Independent Investigator Grant no. 56388, New York Stem Cell Initiative C029157 and C023054, the Dr Brigitt Rok-Potamkin’s Foundation, the Morris Stroud III Center for Study of Quality of Life in Health and Aging (to M.B.) and the American Epilepsy Society (to A.A.).
J.J.M. receives royalties for commercial use of the C-SSRS from the Research Foundation for Mental Hygiene. Work by V.A. related to this paper was completed when she was employed at Columbia University and the New York State Psychiatric Institute; the opinions expressed in this article are the authors’ own and do not reflect the views of the NIH, the Department of Health and Human Services or the United States government. The remaining authors declare no competing interests.
Peer review information
Nature Neuroscience thanks Jeong Ho Lee and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended Data Fig. 1 Relationship among human immature neurons, age, MTLE onset and disease duration.
(a) Dcx + (green) Prox1 + (purple) immature neuron in late stage maturation across Z stacks. Scale bar 10 µm. (b) Correlation between disease duration (yr.) and age at surgery (yr) (N = 17). Two-tailed Pearson Correlation ** P ≤ 0.01. Pearson r = 0.6299 (c) Number of Dcx+ Prox1 cells/mm3 in the Granule cell layer (GCL) with age of onset (yr.) (N = 17). Two-tailed Pearson Correlation ** P ≤ 0.01. Pearson r = 0.7021 (d) Age of onset for cases in which Dcx+ Prox1+ cells were undetected (-) (N = 10) vs detected (+) (N = 7). The graph represents s.e.m. Unpaired two-tailed t-test. * P ≤ 0.05. (e) Correlation between disease duration (yr.) and age of onset (yr.) (N = 17). Pearson Correlation *** P ≤ 0.001. Pearson r = −0.7728 (b-e) Data points marked in red and blue are from cases in which Dcx+ Prox1+ cells were undetected (-) N = 10 and detected (+) N = 7 respectively. (f, g) Number of Dcx+ Prox1+ cells/mm3 in the GCL in (f) female (N = 11) vs male (N = 6) cases, and (g) left (N = 7) vs right (N = 10) hippocampus. The graph represents s.e.m. (h) Magnified view of Dcx+ Prox1+ cells ranging early, mid and late maturation states morphologically. Scale bar: 10 µm. (i) Fraction of Dcx+ Prox1+ cells in various maturation stages in N = 7 cases with Dcx+ Prox1+ cells detected. One-way ANOVA (F 1.115,6.687 = 18.29, p = 0.0036) Tukey’s multiple comparison’s test. * P ≤ 0.05, *** P ≤ 0.001. (j) Fraction of early, mid and late maturation stage Dcx+ Prox1+ immature neurons in each of N = 7 MTLE cases with Dcx+ Prox1+ cells detected. (k) Dcx + (green) PSA-NCAM + (red) cells with late maturation state morphology identified in the GCL of N = 1 MTLE case. (l) Dcx + (green) PSA-NCAM + (red) Prox1 + (purple) cell across Z-planes for image in Fig. 1i lower panel Representative image from staining done in N = 4 cases.
Extended Data Fig. 2 Identifying Dcx + cells as immature astroglia in MTLE tissue.
(a) Dcx+ stellar cells (green) do not co-express markers for granule neurons (Prox1) (N = 17 MTLE cases), mossy cells (GluR2/3) (N = 2 MTLE cases) inhibitory neurons (Gad65 + 67) (N = 2 MTLE cases) and microglia (Iba1) (N = 2 MTLE cases) stained in red. Scale bar 10 µm. (b) Dcx + (green) Prox1- (purple) stellar cells do not co-express PSA-NCAM (red), a marker for immature neuron Scale bar 10 µm. (N = 4 MTLE cases) (c) Dcx+ stellar cells (green) do not co-express ki-67 (red), a marker for cell proliferation (N = 3 MTLE cases) Scale bar 10 µm.
Extended Data Fig. 3 Dcx + stellar cells co-express glial markers in MTLE patients but not in healthy controls.
(a, b) Dcx + (Green) stellar cells co-express glial markers (a) S100β (Red), and (b) GFAP (Red) mostly in the hilus and GCL (marked by arrow). S100β + Dcx- cells and GFAP + Dcx- cells (marked by arrowhead) are present in the ML. N = 5 MTLE cases. Scale bar 50 µm. (c) Dcx + (Green) GFAP + (Red) cells not detected in GCL, hilus and ML of N = 5 control cases.
Extended Data Fig. 4 Neural differentiation from adult MTLE patients.
(a) Upper 3 panels: Tuj1 + (green) GFAP + (red) newborn astroglia (marked by arrows) and Tuj1+ GFAP- cells (marked by arrowheads) present in neural differentiation cultures at 3-week (N = 6) and 6-week (N = 5) differentiation. Lower 3 panels: Tuj1 + (green) Prox1 + (red) newborn granule neurons (marked by arrows) and Tuj1 + Prox1- cells (marked by arrowheads) present in neural differentiation cultures at 3-week (N = 5) and 6-week (N = 5) differentiation. Scale bar: 50 µm (b) Tuj1- GFAP + mature astroglia were rarely identified in N = 3 cases. Scale bar: 50 µm. (c) Percentage of Tuj1- GFAP + mature astroglia at 3 (N = 6) - and 6-week (N = 5) differentiation. Graph represents s.e.m.
Extended Data Fig. 5 Mapping inter-ictal like activity with multi-electrode array (MEA) in DG-I cases.
(a) Illustrative 8×8 and 6×10 60-electrode MEA configuration and hippocampal slice recording of adult human MTLE tissue (4 representative cases from DG-I group). Inter-ictal like activity detected by electrodes covering the dentate gyrus (DG). Red markings overlaying the brightfield slice image and individual electrode recordings corresponds to inter-ictal like activity with comparatively higher amplitude, yellow markings – electrodes detecting comparatively lower amplitude and black markings – electrodes not detecting inter-ictal like activity.
Extended Data Fig. 6 Mapping inter-ictal like activity with multi-electrode array (MEA) in Whole DG-NI cases.
(a) Illustrative 8×8 60-electrode MEA configuration and hippocampal slice recording of adult human MTLE tissue (4 representative cases from Whole DG-NI group lacking activity in the DG). Inter-ictal like activity not detected by electrodes covering the DG. Red markings in the slice picture and MEA electrode layout indicate electrodes detecting comparatively higher amplitude inter-ictal like activity, yellow markings – electrodes detecting comparatively lower amplitude and black markings – electrodes not detecting inter-ictal like activity.
Extended Data Fig. 7 Ectopic immature neurons in MTLE patient hippocampus.
(a) Representative image of Dcx + (green) Prox1 + (purple) cells in the Hilus (left panel) and ML (right panel). Scale bar: 50 µm. (b) Distance of Dcx+ Prox1+ cell from GCL in the hilus and ML of N = 7 MTLE cases. Graph represents s.e.m. (c) Dcx + (green) PSA-NCAM + (red) immature neurons in hilus and ML are not positive for c-fos (Purple) in N = 5 MTLE cases. (d) Dcx + (green) PSA-NCAM + (red) immature neurons that are Arc- and Arc + (Purple) identified in hilus and ML of N = 5 MTLE cases.
Extended Data Fig. 8 Immediate early genes c-fos and Arc in adult MTLE patient hippocampus.
(a) All Dcx + (green) c-fos + (purple) cells co-express S100β (red) (N = 2 cases) (b) Dcx (green) and Arc (red) co-staining determine the relationship between immature cells and inter-ictal like activity. Increased presence of Arc+ cells in the GCL of Sub DG-I compared to Whole DG-NI and Sub DG-NI. Dcx+ astroglia are preferentially localized to the hilus in Sub DG-I (arrowheads). Scale bar: 100 µm (c) Magnified view of Dcx and Arc co-staining. Scale bar 10 µm. Dcx+ atypical astroglial cells (green) are mostly Arc- in whole DG-NI cases and subregions of cases with inter-ictal like activity. (d) Quantification of Arc expression in immature Dcx+ astroglia in whole DG-NI cases (N = 6) and subregions of cases with inter-ictal like activity (N = 5). Data points are from individual MTLE cases, and the graph represents s.e.m.
Supplementary Tables 1–4 with legends.
Rights and permissions
About this article
Cite this article
Ammothumkandy, A., Ravina, K., Wolseley, V. et al. Altered adult neurogenesis and gliogenesis in patients with mesial temporal lobe epilepsy. Nat Neurosci 25, 493–503 (2022). https://doi.org/10.1038/s41593-022-01044-2
This article is cited by
Electroconvulsive therapy—a shocking inducer of neuroplasticity?
Molecular Psychiatry (2023)
Transcranial focused ultrasound-mediated unbinding of phenytoin from plasma proteins for suppression of chronic temporal lobe epilepsy in a rodent model
Scientific Reports (2023)
Morphological brain alterations in dialysis- and non-dialysis-dependent patients with chronic kidney disease
Metabolic Brain Disease (2023)
Astrocytes in the initiation and progression of epilepsy
Nature Reviews Neurology (2022)
Molecular landscapes of human hippocampal immature neurons across lifespan