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Altered adult neurogenesis and gliogenesis in patients with mesial temporal lobe epilepsy

Nature Neuroscience volume 25, pages 493–503 (2022)Cite this article

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Abstract

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.

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Fig. 1: Adult neurogenesis in patients with MTLE declines with disease duration.
Fig. 2: Immature astroglia persist through human MTLE disease duration.
Fig. 3: Generation of newborn granule neurons and astroglia from adult patients with MTLE.
Fig. 4: Newborn neuron behavior with epileptiform activity.
Fig. 5: Alteration of immature astroglia behavior with epileptiform activity.

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Data availability

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.

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Acknowledgements

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.

Funding

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.).

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Authors and Affiliations

  1. Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Aswathy Ammothumkandy, Victoria Wolseley, Luis Corona, Naibo Zhang & Michael A. Bonaguidi

  2. Neurorestoration Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Kristine Ravina, George Nune, Brian Lee, J. A. D. Smith, Christianne Heck, Charles Y. Liu, Jonathan J. Russin & Michael A. Bonaguidi

  3. Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Victoria Wolseley & Robert H. Chow

  4. Division of Molecular Imaging and Neuropathology, NYS Psychiatric Institute, New York, NY, USA

    Alexandria N. Tartt, J. John Mann, Gorazd B. Rosoklija, Victoria Arango, Andrew J. Dwork & Maura Boldrini

  5. Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA

    Pen-Ning Yu, Dong Song, Theodore W. Berger, Robert H. Chow, Charles Y. Liu & Michael A. Bonaguidi

  6. Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    George Nune, Laura Kalayjian & Christianne Heck

  7. Department of Psychiatry, Columbia University, New York, NY, USA

    J. John Mann, Gorazd B. Rosoklija, Victoria Arango, Andrew J. Dwork & Maura Boldrini

  8. Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia

    Gorazd B. Rosoklija & Andrew J. Dwork

  9. Department of Pathology and Cell Biology, Columbia University, New York, NY, USA

    Andrew J. Dwork

  10. Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Brian Lee, Charles Y. Liu & Jonathan J. Russin

  11. Department of Physical Medicine and Rehabilitation, University of Texas Southwestern Medical Center, Dallas, TX, USA

    J. A. D. Smith

  12. Department of Gerontology, University of Southern California, Los Angeles, CA, USA

    Michael A. Bonaguidi

  13. Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, USA

    Michael A. Bonaguidi

  14. Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Michael A. Bonaguidi

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  1. Aswathy Ammothumkandy
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Contributions

A.A. and M.A.B. conceived the project. A.A, J.A.D.S., R.H.C., D.S., T.W.B., C.Y.L., J.J.R., M.B. and M.A.B. designed the experiments. A.A., K.R., V.W., N.Z., A.N.T., L.C. and P.-N.Y. performed the experiments. K.R., A.J.D., G.B.R., M.B. and J.J.M. compiled the clinical information. J.J.R., C.Y.L. and B.L. performed the neurosurgeries. G.N., L.K., C.H., M.B., A.J.D., G.B.R., V.A. and J.J.M. conducted clinical review and assisted with specimen collection. A.A. analyzed and compiled the data. A.A., K.R., A.N.T., M.B. and M.A.B. wrote the manuscript. M.A.B. and M.B. supervised the project.

Corresponding author

Correspondence to Michael A. Bonaguidi.

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Competing interests

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.

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Extended data

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.

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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

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