Please wait a minute...
 Home  About the Journal Editorial Board Aims & Scope Peer Review Policy Subscription Contact us
Early Edition  //  Current Issue  //  Open Special Issues  //  Archives  //  Most Read  //  Most Downloaded  //  Most Cited
Aging and disease    2020, Vol. 11 Issue (6) : 1374-1394     DOI: 10.14336/AD.2020.1020
Orginal Article |
Hippocampal Neural Stem Cell Grafting after Status Epilepticus Alleviates Chronic Epilepsy and Abnormal Plasticity, and Maintains Better Memory and Mood Function
Bharathi Hattiangady1,2,3,4, Ramkumar Kuruba3,4, Bing Shuai1,2,3,4, Remedios Grier3,4, Ashok K Shetty1,2,3,4,*
1Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, TX, USA.
2Research Service, Olin E. Teague Veterans' Medical Center, Central Texas Veterans Health Care System, Temple, TX, USA.
3Department of Surgery (Neurosurgery) Duke University Medical Center, Durham, NC, USA.
4Research and Surgery Services, Durham Veterans Affairs Medical Center, Durham, NC, USA
Download: PDF(2003 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks    

Hippocampal damage after status epilepticus (SE) leads to multiple epileptogenic changes, which lead to chronic temporal lobe epilepsy (TLE). Morbidities such as spontaneous recurrent seizures (SRS) and memory and mood impairments are seen in a significant fraction of SE survivors despite the administration of antiepileptic drugs after SE. We examined the efficacy of bilateral intra-hippocampal grafting of neural stem/progenitor cells (NSCs) derived from the embryonic day 19 rat hippocampi, six days after SE for restraining SE-induced SRS, memory, and mood impairments in the chronic phase. Grafting of NSCs curtailed the progression of SRS at 3-5 months post-SE and reduced the frequency and severity of SRS activity when examined at eight months post-SE. Reduced SRS activity was also associated with improved memory function. Graft-derived cells migrated into different hippocampal cell layers, differentiated into GABA-ergic interneurons, astrocytes, and oligodendrocytes. Significant percentages of graft-derived cells also expressed beneficial neurotrophic factors such as the fibroblast growth factor-2, brain-derived neurotrophic factor, insulin-like growth factor-1 and glial cell line-derived neurotrophic factor. NSC grafting protected neuropeptide Y- and parvalbumin-positive host interneurons, diminished the abnormal migration of newly born neurons, and rescued the reelin+ interneurons in the dentate gyrus. Besides, grafting led to the maintenance of a higher level of normal neurogenesis in the chronic phase after SE and diminished aberrant mossy fiber sprouting in the dentate gyrus. Thus, intrahippocampal grafting of hippocampal NSCs shortly after SE considerably curbed the progression of epileptogenic processes and SRS, which eventually resulted in less severe chronic epilepsy devoid of significant cognitive and mood impairments.

Keywords cell transplantation      cognitive dysfunction      depression      EEG      hippocampal NSCs      memory      neural stem cells      neuroprotection      stem cell grafts      temporal lobe epilepsy     
Corresponding Authors: Shetty Ashok K   
About author:

these authors contributed equally to this work.

Just Accepted Date: 23 October 2020   Issue Date: 19 November 2020
E-mail this article
E-mail Alert
Articles by authors
Hattiangady Bharathi
Kuruba Ramkumar
Shuai Bing
Grier Remedios
Shetty Ashok K
Cite this article:   
Hattiangady Bharathi,Kuruba Ramkumar,Shuai Bing, et al. Hippocampal Neural Stem Cell Grafting after Status Epilepticus Alleviates Chronic Epilepsy and Abnormal Plasticity, and Maintains Better Memory and Mood Function[J]. Aging and disease, 2020, 11(6): 1374-1394.
URL:     OR
Figure 1.  Early grafting of hippocampal neural stem cells (NSCs) reduced spontaneous recurrent seizures (SRS) at three months post-SE, curbed the progression of SRS at 3-5 months post-SE, and restrained the frequency and severity of SRS at 8 months post-SE as revealed by behavioral and EEG quantifications. The bar charts A1-A4 show the frequency of all SRS (A1), stage V SRS (A2), duration of individual SRS (A3), and the percentage of recorded time spent in SRS activity (A4). Note that the overall frequency and intensity of SRS as well as the percentage of time spent in SRS activity were significantly lower in the SE+NSC group (green), in comparison to the SE only(red) and SE+DC (blue) groups at 4 and 5 months post-SE (A1, A2, A4). All SRS activity parameters were mostly comparable between the SE+DC and SE only groups, implying that dead cell grafting after SE did not diminish or exacerbate SRS activity (A1, A2, A4). Also, note the progressive increase in SRS activity over 3-5 months in SE only and SE+DC groups compared to the SE+NSC group where SRS remained constant (A1-A4). Video-EEG recordings and analyses at 8 months post-SE revealed a sustained reduction in SRS at an extended time point after SE (B1-B6). EEG tracings in B1 and B2 show the reduced severity of SRS activity in the SE+NSC group (B2) in comparison to the SE alone group (B1). The bar charts (B3-B6) compare the various EEG data between the SE only and SE+NSC groups at 8 months after SE, which revealed significantly reduced SRS activity for all measured parameters. * p < 0.05. **p < 0.01, *** p < 0.001.
Figure 2.  Early intervention with hippocampal NSC grafting after SE preserved recognition memory function and diminished the depressive-like behavior during the chronic phase of epilepsy. A Novel Object Recognition test (NORT) was used for this test. The cartoon A1-A3 shows the open field box with different objects during the three phases of this test. The bar charts B1-B3 demonstrate the performance of animals in the naïve control (purple), SE only (red), and SE+NSC group (green). Note a significantly higher preference of animals in the naïve control and SE+NSC groups to explore novel object area (NOA) over the familiar object area (FOA) in trial 3 (B1, B3, B4), which implied an ability for recognition memory. In contrast, the animals in the SE only group did not show any preference for either the FOA or NOA in Trial 3 (B2, B4). Note that the total object exploration times were comparable between the three groups (B5). The bar charts C1-C3 show the extent of depressive-like behavior in different groups in a forced swim test (FST). The total time spent in immobility during the FST was used as a measure of depressive-like behavior. Note that the times spent in floating were significantly greater in SE only animals at first 5 minutes (C1), last 5 minutes (C2), or for the entire duration of 10 minutes (C3). In contrast, the duration of immobility in the SE+NSC group was highly comparable to that of animals in the naïve control group but significantly lower than the SE only group in different segments and during the entire duration of the test, indicating a graft-mediated reduction in depressive-like behavior (C1-C3). *p<0.05; **p<0.01; ***p<0.001.
Figure 3.  Cells derived from neural stem cell (NSC) grafts displayed long-term survival and differentiated into all three neural cell types in the host hippocampus that underwent SE-induced injury. The top panel (A1-A3) shows the 5'-Chloro-2'-deoxyuridine CldU-positive graft-derived cells in the host hippocampus at ~9 months post-grafting (A1). A2 and A3 are magnified views of regions from A1, depicting the distribution of CldU+ cells in the graft core (A2) and neighboring dentate granule cell layer (GCL, A3). B1-C4 demonstrate samples of confocal Z section images visualizing graft-derived neurons positive for CldU and NeuN in the CA3 region (B1-B3) and the GCL (C1-C3). B4 and C4 show orthogonal views of graft-derived neurons expressing CldU-NeuN. The bar chart D depicts the overall neuronal differentiation of graft-derived cells in the GCL (neurogenic) and the graft core (D). Figures E1-E4 demonstrate graft-derived CldU+ cells expressing gamma-aminobutyric acid (GABA). E4 shows an orthogonal view of a graft-derived interneuron expressing CldU and GABA. The bar chart F depicts the overall % of graft-derived cells differentiating into GABA-ergic interneurons. Figures G1-I4 show the differentiation of graft-derived CldU+ cells into S-100ß+ mature astrocytes (G1-G3), NG2+ oligodendrocyte progenitors (G1-G3), and O4+ oligodendrocytes (I1-I3) in the host hippocampus. G4, H4, and I4 show the orthogonal view of a graft-derived astrocyte (G4), an oligodendrocyte progenitor cell (H4), and an oligodendrocyte (I4). The bar chart J shows the percentage of S-100ß+ astrocytes, NG2+ oligodendrocyte progenitors, and oligodendrocytes among graft-derived cells. Scale bars: A1, 200 µm; A2 and A3, 50 µm; B1-E4, G1-G3, H1-H3, and I1-I4, 10 µm; G4 and H4, 5 µm. DH, dentate hilus.
Figure 4.  Cells derived from neural stem cell (NSC) grafts expressed multiple neurotrophic factors in the host hippocampus when examined at 9 months post grafting. A1-E3 show dual immunofluorescence confocal images for 5'-Chloro-2'-deoxyuridine (CldU) and fibroblast growth factor-2 (FGF-2) (A1-A3), CldU and insulin-like growth factor-1 (IGF-1) (B1-B3), CldU and brain-derived neurotrophic factor (BDNF) (D1-D3), and CldU and glial cell line-derived neurotrophic factor (GDNF) (E1-E3). The bar chart C depicts the % of the graft-derived cells expressing FGF-2 and IGF-1, whereas the bar chart F shows the percentages of graft-derived cells expressing BDNF and GDNF. White arrows in A1-E3 show examples of dual-labeled cells. Scale bars: = A3, B3, D3, and E3, 10 µm.
Figure 5.  Early neural stem cell (NSC) grafting after SE preserved higher numbers of interneurons in the dentate hilus (DH) of the host hippocampus. The panels on the left show the neuropeptide Y (NPY)-positive interneurons in the dentate gyrus (DG) of animals belonging to the naïve control (A1), SE only (B1), or SE+NSC (C1) groups. A2, B2, and C2 are magnified views of regions from A1, B1, and C1, respectively, showing the morphology of NPY+ interneurons. Note significant preservation of NPY+ neurons in the SE+NSC group exhibiting hypertrophy (C2). The bar chart D compares the number of NPY+ interneurons in the DG between different groups. The panels on the right show the parvalbumin (PV)-positive interneurons in the DG of animals belonging to naïve control (E1), SE only group (F1), or SE+NSC (G1) groups. E2, F2, and G2 are magnified views of regions from F1, G1, and H1, respectively. The Bar chart H compares the number of PV+ interneurons in the DG between different groups. *, p<0.05; **, p<0.01. Scale bars: A1, B1, C1, E1, F1, and G1, 200 µm; A2, B2, and C2, 50 µm; E2, F2, and G2, 100 µm. GCL, granule cell layer.
Figure 6.  Neural stem cell (NSC) grafting after SE promoted a higher level of normal neurogenesis and reduced the aberrant neurogenesis in the DG during the chronic epilepsy phase. The top panel shows the doublecortin (DCX)-positive newly born neurons in the DG of animals belonging to the control (A1), SE only (B1), and SE+NSC (C1) groups. A2, B2, C2 are magnified views of regions from A1, B1, C1, respectively. Note the dramatically declined normal neurogenesis and prominent aberrant neurogenesis in the dentate hilus (DH) of SE only group(B1-B2) and a preserved dentate neurogenesis and reduced abnormal neurogenesis in the SE+NSC graft group (C1-C2). The bar chart D compares the number of DCX+ neurons in the dentate gyrus (DG) between the three groups. Note a substantially declined normal dentate neurogenesis in the SE only group, in comparison to the naïve group and a much higher level of neurogenesis in the SE+NSC group (D) at ~9 months post-SE. The panel E-G shows prox-1+ dentate granule cell in the DH of animals belonging to the naïve control (E), SE only (F), and SE+NSC (G) groups. The bar chart H compares the number of prox1+ cells in the DH between the three groups. Note significantly reduced Prox1+ cells in the SE+NSC group, implying the long-term benefits of grafting in reducing the extent of abnormal dentate neurogenesis. The lower panel (I, J, K) shows reelin+ interneurons in animals belonging to the naïve control (I), SE only (j), and SE+NSC (K) groups. Bar chart L compares reelin+ interneurons between the three groups. Note that, in comparison to SE only group, the SE+NSC group displayed better preservation of reelin+ interneurons in the DH and when the entire DG is taken in its entirety (L). *p<0.05; **p<0.01; ***p<0.001. Scale bars, I, J, and K, 200 µm, A1, B1, and C1, 100 µm, A2, B2, C2, E, F, and G, 50 µm. GCL, granule cell layer; SGZ, Subgranular zone.
Figure 7.  Neural stem cell grafting after SE reduced the extent of aberrant mossy fiber sprouting into the dentate supragranular layer (DSGL) when examined at 9 months post-SE. The ZNT-3 immunostaining was performed to visualize the extent of aberrant mossy fiber sprouting in the SE only (A1-A4) and SE+NSC groups (B1-B4). Note the highly conspicuous aberrant mossy fiber sprouting with dark bands in the upper blade (A2), the lower blade (A3), and the crest (A4) of the granule cell layer (GCL) in the SE only group, and greatly diminished sprouting in the SE+NSC group (B2, B3, B4). The bar charts C1, C2, C3 compare the area fraction of sprouted mossy fibers between the SE only and SE+NSC groups. Note that the intervention with hippocampal NSC grafting has significantly reduced the extent of aberrant mossy fiber sprouting in all three regions of the dentate gyrus (DG) in comparison to the SE only group (C1-C3). **, p<0.01; ***, p<0.001. Scale bars: A1 and B1, 500 µm, A2-B4, 100 µm. AF, area fraction; DH, dentate hilus; GCL, granule cell layer; SGL, supragranular layer; UB, upper blade; LB, lower blade.
Figure 8.  The cartoon depicts a summary of the experimental design, results, and significant findings. The top portion shows the induction of status epilepticus (SE) in F344 rats through kainic acid (KA) injections. The top right side of the figure illustrates the dissection of embryonic day 19 (E19) rat hippocampi, trituration of hippocampal tissues, expansion of neural stem cells (NSCs) as neurospheres, and labeling of NSCs with 5'-Chloro-2'-deoxyuridine (CldU) in vitro. Neurospheres were triturated into a cell suspension before grafting into the hippocampus at six days post-SE. The left side of the figure shows the timeline for various analyses performed in the study, whereas the middle portion of the figure illustrates multiple changes in the SE alone group and the SE + NSC group. The summary of results is listed on the lower right portion of the figure.
[1] Devinsky O (2004). Diagnosis and treatment of temporal lobe epilepsy. Rev Neurol Dis, 1:2-9.
[2] Strine TW, Kobau R, Chapman DP, Thurman DJ, Price P, Balluz LS (2005). Psychological distress, comorbidities, and health behaviors among U.S. adults with seizures: results from the 2002 National Health Interview Survey. Epilepsia, 46:1133-1139.
[3] Mikulecka A, Druga R, Stuchlík A, Mareš P, Kubová H (2019). Comorbidities of early-onset temporal epilepsy: Cognitive, social, emotional, and morphologic dimensions. Exp Neurol, 320:113005.
[4] D'Alessio L, Konopka H, Solís P, (2019). Depression and Temporal Lobe Epilepsy: Expression Pattern of Calbindin Immunoreactivity in Hippocampal Dentate Gyrus of Patients Who Underwent Epilepsy Surgery with and without Comorbid Depression. Behav Neurol, 2019: 7396793.
[5] Postma TS, Cury C, Baxendale S, Thompson PJ, Cano-López I, Tisi J, et al. (2020). Hippocampal Shape Is Associated with Memory Deficits in Temporal Lobe Epilepsy. Ann Neurol, 88:170-182.
[6] Harvey AS, Berkovic SF, Wrennall JA, Hopkins IJ (1997). Temporal lobe epilepsy in childhood: clinical, EEG, and neuroimaging findings and syndrome classification in a cohort with new-onset seizures. Neurology, 49: 960-968.
[7] Fisher PD, Sperber EF, Moshe SL (1998). Hippocampal sclerosis revisited. Brain Dev, 20: 563-573.
[8] RaoMS, Hattiangady B, Reddy DS, Shetty AK (2006). Hippocampal neurodegeneration, spontaneous seizures, and mossy fiber sprouting in the F344 rat model of temporal lobe epilepsy. J Neurosci Res, 83: 1088-105.
[9] RaoMS, Hattiangady B, Rai KS, Shetty AK (2007). Strategies for promoting anti-seizure effects of fetal hippocampal cells grafted into the hippocampus of rats exhibiting chronic temporal lobe epilepsy. Neurobiol Dis, 27:117-132.
[10] Rao MS, Hattiangady B, Shetty AK (2008). Status epilepticus during old age is not associated with enhanced hippocampal neurogenesis. Hippocampus, 18: 931-944.
[11] Hattiangady B, Rao MS, Shetty AK (2008). Grafting of striatal precursor cells into the hippocampus shortly after status epilepticus restrains chronic temporal lobe epilepsy. Exp Neurol, 212: 468-481.
[12] Hattiangady B, Kuruba R, Shetty AK (2011). Acute seizures in old age leads to a greater loss of CA1 pyramidal neurons, an increased propensity for developing chronic TLE, and a severe cognitive dysfunction. Aging Dis, 2:1-17.
[13] Kuruba R, Hattiangady B, Parihar VK, Shuai B, Shetty AK (2011). Differential susceptibility of interneurons expressing neuropeptide Y or parvalbumin in the aged hippocampus to acute seizure activity. PLoS One, 6: e24493.
[14] Long Q, Upadhya D, Hattiangady B, Kim DK, An SY, Shuai B, et al. (2017). Intranasal MSC-derived A1-exosomes ease inflammation and prevent abnormal neurogenesis and memory dysfunction after status epilepticus. Proc Natl Acad Sci USA, 114: E3536-E3545.
[15] Manford M, Hart YM, Sander JW, Shorvon SD (1992). The National General Practice Study of Epilepsy (NGPSE): partial seizure patterns in a general population. Neurology, 42:1911-1917.
[16] Litt B, Esteller R, Echauz J, D'Alessandro M, Shor R, Henry T, et al. (2001). Epileptic seizures may begin hours in advance of clinical onset: a report of five patients. Neuron, 30:51-64.
[17] McKeown MJ, McNamara JO (2001). When do epileptic seizures really begin? Neuron,30:1-3.
[18] Shetty AK (2011). Progress in cell grafting therapy for temporal lobe epilepsy. Neurotherapeutics, 8:721-735.
[19] Shetty AK (2014). Hippocampal injury-induced cognitive and mood dysfunction, altered neurogenesis, and epilepsy: can early neural stem cell grafting intervention provide protection? Epilepsy Behav, 38:117-124.
[20] Shetty AK, Upadhya D (2016). GABA-ergic cell therapy for epilepsy: Advances, limitations, and challenges. Neurosci Biobehav Rev, 62:35-47.
[21] Hattiangady B, Shetty AK (2012). Neural stem cell grafting counteracts hippocampal injury-mediated impairments in mood, memory, and neurogenesis. Stem Cells Transl Med, 1:696-708.
[22] Waldau B, Hattiangady B, Kuruba R, Shetty AK (2010). Medial ganglionic eminence-derived neural stem cell grafts ease spontaneous seizures and restore GDNF expression in a rat model of chronic temporal lobe epilepsy. Stem Cells, 28:1153-1164.
[23] Shetty AK, Hattiangady B (2016). Grafted Subventricular Zone Neural Stem Cells Display Robust Engraftment and Similar Differentiation Properties and Form New Neurogenic Niches in the Young and Aged Hippocampus. Stem Cells Transl Med, 5:1204-1215.
[24] Shindo A, Nakamura T, Matsumoto Y, Kawai N, Okano H, Nagao S, et al. (2010). Seizure suppression in amygdala-kindled mice by transplantation of neural stem/progenitor cells derived from mouse embryonic stem cells. Neurol Med Chir (Tokyo), 50:98-105.
[25] Palmer TD, Markakis EA, Willhoite AR, Safar F, Gage F H (1999). Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J Neurosci, 19:8487-8497.
[26] Zimmermann T, Remmers F, Lutz B, Leschik J (2016). ESC-Derived BDNF-Overexpressing Neural Progenitors Differentially Promote Recovery in Huntington's Disease Models by Enhanced Striatal Differentiation. Stem Cell Reports, 7:693-706.
[27] Rosati J, Ferrari D, Altieri F, Tardivo S, Ricciolini C, Fusilli C, et al. (2018). Establishment of stable iPS-derived human neural stem cell lines suitable for cell therapies. Cell Death Dis, 9: 937.
[28] Tang C, Wang M, Wang P, Wang L, Wu Q, Guo W (2019). Neural Stem Cells Behave as a Functional Niche for the Maturation of Newborn Neurons through the Secretion of PTN. Neuron, 101:32-44.
[29] Lippert T, Gelineau L, Napoli E, Borlongan CV (2018). Harnessing neural stem cells for treating psychiatric symptoms associated with fetal alcohol spectrum disorder and epilepsy. Prog Neuropsychopharmacol Biol Psychiatry, 80:10-22.
[30] Rao MS, Hattiangady B, Shetty AK (2006). Fetal hippocampal CA3 cell grafts enriched with FGF-2 and BDNF exhibit robust long-term survival and integration and suppress aberrant mossy fiber sprouting in the injured middle-aged hippocampus. Neurobiol Dis, 21: 276-290.
[31] Hattiangady B, Shetty AK (2011). Neural stem cell grafting in an animal model of chronic temporal lobe epilepsy. Curr Protoc Stem Cell Biol, Chapter 2: Unit2D 7.
[32] Upadhya D, Hattiangady B, Shetty GA, Zanirati G, Kodali M, Shetty AK (2016). Neural Stem Cell or Human Induced Pluripotent Stem Cell-Derived GABA-ergic Progenitor Cell Grafting in an Animal Model of Chronic Temporal Lobe Epilepsy. Curr Protoc Stem Cell Biol, 38:2D.7.1-2D.7.47.
[33] Shetty AK, Hattiangady B (2013). Postnatal age governs the extent of differentiation of hippocampal CA1 and CA3 subfield neural stem/progenitor cells into neurons and oligodendrocytes. Int J Dev Neurosci, 31:646-656.
[34] Upadhya D, Hattiangady B, Castro OW, Shuai B, Kodali M, Attaluri S, et al. (2019). Human induced pluripotent stem cell-derived MGE cell grafting after status epilepticus attenuates chronic epilepsy and comorbidities via synaptic integration. Proc Natl Acad Sci USA, 116:287-296.
[35] Parihar VK, Hattiangady B, Kuruba R, Shuai B, Shetty AK (2011). Predictable chronic mild stress improves mood, hippocampal neurogenesis, and memory. Mol Psychiatry, 16: 171-183.
[36] Hattiangady B, Mishra V, Kodali M, Shuai B, Rao X, Shetty AK (2014). Object location and object recognition memory impairments, motivation deficits, and depression in a model of Gulf War illness. Front Behav Neurosci, 8:78.
[37] Parihar VK, Hattiangady B, Shuai B, Shetty AK (2013). Mood and memory deficits in a model of Gulf War illness are linked with reduced neurogenesis, partial neuron loss, and mild inflammation in the hippocampus. Neuropsychopharmacology, 38: 2348-2362.
[38] Porsolt RD, Le Pichon M, Jalfre M (1977). Depression: a new animal model sensitive to antidepressant treatments. Nature, 266: 730-732.
[39] Slattery DA, Cryan JF (2012). Using the rat forced swim test to assess antidepressant-like activity in rodents. Nat Protoc, 7:1009-1014.
[40] Kodali M, Parihar VK, Hattiangady B, Mishra V, Shuai B, Shetty AK (2015). Resveratrol prevents age-related memory and mood dysfunction with increased hippocampal neurogenesis and microvasculature and reduced glial activation. Sci Rep, 28:8075.
[41] Upadhya D, Kodali M, Gitai D, Castro OW, Zanirati G, Upadhya R, et al. (2019). A Model of Chronic Temporal Lobe Epilepsy Presenting Constantly Rhythmic and Robust Spontaneous Seizures, Comorbidities, and Hippocampal Neuropathology. Aging Dis, 10:915-936.
[42] Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS, Lowenstein DH (1997). Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci, 17:3727-3738.
[43] HattiangadyB RaoMS, Shetty AK (2004). Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus. Neurobiol Dis, 17: 473-490.
[44] Hattiangady B, Shetty AK (2010). Decreased neuronal differentiation of newly generated cells underlies reduced hippocampal neurogenesis in chronic temporal lobe epilepsy. Hippocampus, 20:97-112.
[45] Gong C, Wang TW, Huang HS, Parent JM (2007). Reelin regulates neuronal progenitor migration in intact and epileptic hippocampus. J Neurosci, 27:1803-1811.
[46] de Lanerolle NC, Kim JH, Robbins RJ, Spencer DD (1989). Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy. Brain Res, 495:387-395.
[47] Hirsch JC, Agassandian C, Merchán-Pérez A, Ben-Ari Y, DeFelipe J, Esclapez M, et al. (1999). Deficit of quantal release of GABA in experimental models of temporal lobe epilepsy. Nat Neurosci, 2: 499-500.
[48] Shetty AK, Turner DA (2000). Fetal hippocampal grafts containing CA3 cells restore host hippocampal glutamate decarboxylase-positive interneuron numbers in a rat model of temporal lobe epilepsy. J Neurosci, 20:8788-8801.
[49] Kobayashi M, Buckmaster PS (2003). Reduced Inhibition of dentate granule cells in a model of temporal lobe epilepsy. J Neurosci, 23:2440-2452.
[50] Maisano X, Litvina E, Tagliatela S, Aaron GB, Grabel LB, Naegele JR (2012). Differentiation and functional incorporation of embryonic stem cell-derived GABAergic interneurons in the dentate gyrus of mice with temporal lobe epilepsy. J Neurosci, 32:46-61.
[51] Hunt RF, Girskis KM, Rubenstein JL, Alvarez-Buylla A, Baraban SC (2013). GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior. Nat Neurosci, 16:692-697.
[52] Casalia ML, Howard MA, Baraban SC (2017). Persistent seizure control in epileptic mice transplanted with gamma-aminobutyric acid progenitors. Ann Neurol, 82:530-542.
[53] Kanter-Schlifke I, Fjord-Larsen L, Kusk P, Angehagen M, Wahlberg L, Kokaia M (2009). GDNF released from encapsulated cells suppresses seizure activity in the epileptic hippocampus. Exp Neurol,216:413-419.
[54] Nanobashvili A, Melin E, Emerich D, Tornøe J, Simonato M, Wahlberg, et al. (2019). Unilateral ex vivo gene therapy by GDNF in epileptic rats. Gene Ther, 26:65-74.
[55] Paolone G, Falcicchia C, Lovisari F, Kokaia M, Bell WJ, Fradet T, et al. (2019). Long-Term, Targeted Delivery of GDNF from Encapsulated Cells Is Neuroprotective and Reduces Seizures in the Pilocarpine Model of Epilepsy. J Neurosci, 39:2144-2156.
[56] Miltiadous P, Stamatakis A, Koutsoudaki PN, Tiniakos DG, Stylianopoulou F (2011). IGF-I ameliorates hippocampal neurodegeneration and protects against cognitive deficits in an animal model of temporal lobe epilepsy. Exp Neurol, 231:223-235.
[57] Paradiso B, Marconi P, Zucchini S, Berto E, Binaschi A, Bozacet A, et al. (2009). Localized delivery of fibroblast growth factor-2 and brain-derived neurotrophic factor reduces spontaneous seizures in an epilepsy model. Proc Natl Acad Sci U S A, 106:7191-7196.
[58] Iyengar SS, LaFrancois JJ, Friedman D, Drew LJ, Denny CA, Burghardt NS, et al. (2015). Suppression of adult neurogenesis increases the acute effects of kainic acid. Exp Neurol, 264:135-149.
[59] Jain S, LaFrancois JJ, Botterill JJ, Alcantara-Gonzalez D, Scharfman HE (2019). Adult neurogenesis in the mouse dentate gyrus protects the hippocampus from neuronal injury following severe seizures. Hippocampus, 29: 683-709.
[60] Cho KO, Lybrand ZR, Ito N, Brulet R, Tafacory F, Zhang L, et al. (2015). Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat Commun, 6:6606.
[61] Varma P, Brulet R, Zhang L, Hsieh J (2019). Targeting seizure-induced neurogenesis in a clinically relevant time period leads to transient but not persistent seizure reduction. J Neurosci, 39: 7019-7028.
[62] Shetty AK, Turner DA (1999). Neurite outgrowth from progeny of epidermal growth factor-responsive hippocampal stem cells is significantly less robust than from fetal hippocampal cells following grafting onto organotypic hippocampal slice cultures: effect of brain-derived neurotrophic factor. J Neurobiol, 38:391-413.
[63] Buckmaster PS (2012). Mossy Fiber Sprouting in the Dentate Gyrus. In: NoebelsJL, AvoliM, RogawskiMA, OlsenRW, Delgado-EscuetaAV, editors. Jasper's Basic Mechanisms of the Epilepsies, Bethesda (MD): National Center for Biotechnology Information (US), 150.
[64] Wuarin JP, Dudek FE (2001). Excitatory synaptic input to granule cells increases with time after kainate treatment. J Neurophysiol, 85:1067-1077.
[65] Feng L, Molnar P, Nadler JV (2003). Short-term frequency-dependent plasticity at recurrent mossy fiber synapses of the epileptic brain. J Neurosci, 23:5381-5390.
[66] Scharfman HE, Sollas AL, Berger RE, Goodman JH (2003). Electrophysiological evidence of monosynaptic excitatory transmission between granule cells after seizure-induced mossy fiber sprouting. J Neurophysiol, 90:2536-2547.
[67] Epsztein J, Represa A, Jorquera I, Ben-Ari Y, Crépel V (2005). Recurrent mossy fibers establish aberrant kainate receptor-operated synapses on granule cells from epileptic rats. J Neurosci, 25:8229-8239.
[68] Shetty AK, Zaman V, Hattiangady B (2005). Repair of the injured adult hippocampus through graft-mediated modulation of the plasticity of the dentate gyrus in a rat model of temporal lobe epilepsy. J Neurosci, 25:8391-8401.
[69] Sloviter RS, Zappone CA, Harvey BD, Frotscher M (2006). Kainic acid-induced recurrent mossy fiber innervation of dentate gyrus inhibitory interneurons: possible anatomical substrate of granule cell hyper-inhibition in chronically epileptic rats. J Comp Neurol, 494:944-960.
[70] Sutula T, He XX, Cavazos J, G Scott (1988). Synaptic reorganization in the hippocampus induced by abnormal functional activity. Science. 239:1147-1150.
[71] Stringer JL, Agarwal KS, Dure LS (1997). Is cell death necessary for hippocampal mossy fiber sprouting? Epilepsy Res, 27:67-76.
[72] Holmes GL, Gairsa JL, Chevassus-Au-Louis N, Ben-Ari Y (1998). Consequences of neonatal seizures in the rat: morphological and behavioral effects. Ann Neurol, 44:845-857.
[73] Vaidya VA, Siuciak JA, Du F, Duman RS (1999). Hippocampal mossy fiber sprouting induced by chronic electroconvulsive seizures. Neuroscience, 89:157-166.
[74] Bender RA, Dubé C, Gonzalez-Vega R, Mina EW, Baram TZ (2003). Mossy fiber plasticity and enhanced hippocampal excitability, without hippocampal cell loss or altered neurogenesis, in an animal model of prolonged febrile seizures. Hippocampus, 13:399-412.
[75] Jiao Y, Nadler JV (2007). Stereological analysis of GluR2-immunoreactive hilar neurons in the pilocarpine model of temporal lobe epilepsy: correlation of cell loss with mossy fiber sprouting. Exp Neurol, 205:569-582.
[76] Noe FM, Sørensen AT, Kokaia M, Vezzani A, Noebels JL, Avoli M, et al.(2012). Gene therapy of focal onset epilepsy using adeno-associated virus vector-mediated overexpression of neuropeptide Y. In: Gene therapy of focal onset epilepsy using adeno-associated virus vector-mediated overexpression of neuropeptide Y. In: NoebelsJL editors. Jasper's Basic Mechanisms of the Epilepsies. Bethesda (MD): National Center for Biotechnology Information (US), 100.
[77] Powell KL, Fitzgerald X, Shallue C, Jovanovska V, Klugmann M, Jonquieres GV, et al. (2018). Gene therapy mediated seizure suppression in Genetic Generalized Epilepsy: Neuropeptide Y overexpression in a rat model. Neurobiol Dis, 113:23-32.
[78] Wickham J, Ledri M, Bengzon J, Jespersen B, Pinborg LH, Englund E, et al. (2019). Inhibition of epileptiform activity by neuropeptide Y in brain tissue from drug-resistant temporal lobe epilepsy patients. Sci Rep, 9:19393.
[79] Dutton SB, Makinson CD, Papale LA, Shankar A, Balakrishnan B, Nakazawa K, et al. (2013). Preferential inactivation of Scn1a in parvalbumin interneurons increases seizure susceptibility. Neurobiol Dis, 49:211-220.
[80] Drexel M, Romanov RA, Wood J, Weger S, Heilbronn R, Wulff P, et al. (2017). Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice. J Neurosci, 37:8166-8179.
[81] Kron MM, Zhang H, Parent JM (2010). The developmental stage of dentate granule cells dictates their contribution to seizure-induced plasticity. J Neurosci, 30:2051-2059.
[82] Kanner AM (2016). Psychiatric comorbidities in epilepsy: Should they be considered in the classification of epileptic disorders? Epilepsy Behav, 64:306-308.
[83] Lenck-Santini PP, Scott RC (2015). Mechanisms Responsible for Cognitive Impairment in Epilepsy Cold Spring Harb Perspect Med, 5:a022772.
[84] Deng X, Jia H, Yang Z, Li G, Sun S (2011). Correlation study on expression of GST-pi protein in brain tissue and peripheral blood of epilepsy rats induced by pilocarpine. J Huazhong Univ Sci Technolog Med Sci, 31:701.
[85] Imayoshi I, Sakamoto M, Ohtsuka T, Takao K, Miyakawa T, Yamaguchi M, et al. (2008). Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat Neurosci, 11:1153-1161.
[86] Kozareva DA, Foley T, Moloney GM, Cryan JF, Nolan YM (2019). TLX knockdown in the dorsal dentate gyrus of juvenile rats differentially affects adolescent and adult behaviour. Behav Brain Res, 360:36-50.
[87] Miller SM, Sahay A (2019). Functions of adult-born neurons in hippocampal memory interference and indexing. Nat Neurosci, 22:1565-1575.
[88] Snyder JS, Drew MR (2020). Functional neurogenesis over the years. Behav Brain Res, 382:112470.
[89] Planchez B, Surget A, Belzung C (2020). Adult hippocampal neurogenesis and antidepressants effects. Curr Opin Pharmacol, 50:88-95.
[90] Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA (2011). Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature, 476:458-461.
[91] Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawaet S, et al. (2003). Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science, 301: 805-809.
[92] Eisch AJ, Petrik D (2012). Depression and hippocampal neurogenesis: a road to remission? Science, 338:72-75
[93] Sorensen AT, Kanter-Schlifke I, Carli M, Balducci C, Noe F, During MJ, et al. (2008). NPY gene transfer in the hippocampus attenuates synaptic plasticity and learning. Hippocampus,18:564-574.
[94] Gelfo F, Tirassa P, De Bartolo P, Croce N, Bernardini S, Caltagirone C, et al. (2012). NPY intraperitoneal injections produce antidepressant-like effects and downregulate BDNF in the rat hypothalamus. CNS Neurosci Ther, 18:487-492.
[95] Zaben MJ, Gray WP (2013). Neuropeptides and hippocampal neurogenesis. Neuropeptides, 47:431-438.
[96] Murray AJ, Sauer JF, Riedel G, McClure C, Ansel L, Cheyne L, et al. (2011). Parvalbumin-positive CA1 interneurons are required for spatial working but not for reference memory. Nat Neurosci, 14:297-299.
[97] Klausberger T, Marton LF, O'Neill J, Huck JHJ, Dalezios Y, Fuentealba P, et al. (2005). Complementary roles of cholecystokinin- and parvalbumin-expressing GABAergic neurons in hippocampal network oscillations. J Neurosci, 25:9782-9793.
[98] Korotkova T, Fuchs EC, Ponomarenko A, von Engelhardt J, Monyer H (2010). NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory. Neuron, 68:557-569.
[99] Pertusa M, García-Matas S, Mammeri H, Adell A, Rodrigo T, Mallet J, et al. (2008). Expression of GDNF transgene in astrocytes improves cognitive deficits in aged rats. Neurobiol Aging, 29:1366-1379.
[100] Kiyota T, Ingraham KL, Jacobsen MT, Xiong H, Ikezu T (2011). FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer's disease and has therapeutic implications for neurocognitive disorders. Proc Natl Acad Sci U S A, 108: E1339-1348.
[101] Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Müller F, Loring JF, et al. (2009). Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci U S A, 106:13594-13599.
[102] Mitschelen M, Yan H, Farley JA, Warrington JP, Han S, Hereñú CB, et al. (2011). Long-term deficiency of circulating and hippocampal insulin-like growth factor I induces depressive behavior in adult mice: a potential model of geriatric depression. Neuroscience, 185:50-60.
[103] Perez JA, Clinton SM, Turner CA, Watson SJ, Akil H (2009). A new role for FGF2 as an endogenous inhibitor of anxiety. J Neurosci, 29:6379-6387.
[104] Schmidt HD, Duman RS (2010). Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models. Neuropsychopharmacology, 35:2378-2391.
[1] Supplementary data Download
[1] Xuan Li,Ya Feng,Xi-Xi Wang,Daniel Truong,Yun-Cheng Wu. The Critical Role of SIRT1 in Parkinson’s Disease: Mechanism and Therapeutic Considerations[J]. Aging and disease, 2020, 11(6): 1608-1622.
[2] Anwen Shao,Danfeng Lin,Lingling Wang,Sheng Tu,Cameron Lenahan,Jianmin Zhang. Oxidative Stress at the Crossroads of Aging, Stroke and Depression[J]. Aging and disease, 2020, 11(6): 1537-1566.
[3] Longfei Wu,Mitchell Huber,Di Wu,Jian Chen,Ming Li,Yuchuan Ding,Xunming Ji. Intra-arterial Cold Saline Infusion in Stroke: Historical Evolution and Future Prospects[J]. Aging and disease, 2020, 11(6): 1527-1536.
[4] Jing Zhong,Jun Li,Changhong Miao,Zhiyi Zuo. A Novel Individual-based Determination of Postoperative Cognitive Dysfunction in Mice[J]. Aging and disease, 2020, 11(5): 1133-1145.
[5] Dengyang Han,Zhengqian Li,Taotao Liu,Ning Yang,Yue Li,Jindan He,Min Qian,Zhongshen Kuang,Wen Zhang,Cheng Ni,Xiangyang Guo. Prebiotics Regulation of Intestinal Microbiota Attenuates Cognitive Dysfunction Induced by Surgery Stimulation in APP/PS1 Mice[J]. Aging and disease, 2020, 11(5): 1029-1045.
[6] Seong Gak Jeon, Anji Yoo, Dong Wook Chun, Sang Bum Hong, Hyunju Chung, Jin-il Kim, Minho Moon. The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer’s Disease-related Pathogenesis[J]. Aging and disease, 2020, 11(3): 705-724.
[7] Hefeng Zhou, Shengnan Li, Chuwen Li, Xuanjun Yang, Haitao Li, Hanbing Zhong, Jia-Hong Lu, Simon Ming-Yuen Lee. Oxyphylla A Promotes Degradation of α-Synuclein for Neuroprotection via Activation of Immunoproteasome[J]. Aging and disease, 2020, 11(3): 559-574.
[8] Selçuk Öztürk, Ayşe Eser Elçin, Yaşar Murat Elçin. Mesenchymal Stem Cells for Coronavirus (COVID-19)-Induced Pneumonia: Revisiting the Paracrine Hypothesis with New Hopes?[J]. Aging and disease, 2020, 11(3): 477-479.
[9] Zikuan Leng, Rongjia Zhu, Wei Hou, Yingmei Feng, Yanlei Yang, Qin Han, Guangliang Shan, Fanyan Meng, Dongshu Du, Shihua Wang, Junfen Fan, Wenjing Wang, Luchan Deng, Hongbo Shi, Hongjun Li, Zhongjie Hu, Fengchun Zhang, Jinming Gao, Hongjian Liu, Xiaoxia Li, Yangyang Zhao, Kan Yin, Xijing He, Zhengchao Gao, Yibin Wang, Bo Yang, Ronghua Jin, Ilia Stambler, Lee Wei Lim, Huanxing Su, Alexey Moskalev, Antonio Cano, Sasanka Chakrabarti, Kyung-Jin Min, Georgina Ellison-Hughes, Calogero Caruso, Kunlin Jin, Robert Chunhua Zhao. Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia[J]. Aging and disease, 2020, 11(2): 216-228.
[10] Heng Ai, Weiqing Fang, Hanyi Hu, Xupang Hu, Wen Lu. Antidiabetic Drug Metformin Ameliorates Depressive-Like Behavior in Mice with Chronic Restraint Stress via Activation of AMP-Activated Protein Kinase[J]. Aging and disease, 2020, 11(1): 31-43.
[11] Weiwei Zhong, Yan Yuan, Xiaohuan Gu, Samuel In-young Kim, Ryan Chin, Modupe Loye, Thomas A Dix, Ling Wei, Shan Ping Yu. Neuropsychological Deficits Chronically Developed after Focal Ischemic Stroke and Beneficial Effects of Pharmacological Hypothermia in the Mouse[J]. Aging and disease, 2020, 11(1): 1-16.
[12] Shawn Zheng Kai Tan, Man-Lung Fung, Junhao Koh, Ying-Shing Chan, Lee Wei Lim. The Paradoxical Effect of Deep Brain Stimulation on Memory[J]. Aging and disease, 2020, 11(1): 179-190.
[13] Zhongfeng Liu, Xuan Wang, Kewen Jiang, Xunming Ji, Y. Alex Zhang, Zhiguo Chen. TNFα-induced Up-regulation of Ascl2 Affects the Differentiation and Proliferation of Neural Stem Cells[J]. Aging and disease, 2019, 10(6): 1207-1220.
[14] Dinesh Upadhya, Maheedhar Kodali, Daniel Gitai, Olagide W Castro, Gabriele Zanirati, Raghavendra Upadhya, Sahithi Attaluri, Eeshika Mitra, Bing Shuai, Bharathi Hattiangady, Ashok K Shetty. A Model of Chronic Temporal Lobe Epilepsy Presenting Constantly Rhythmic and Robust Spontaneous Seizures, Co-morbidities and Hippocampal Neuropathology[J]. Aging and disease, 2019, 10(5): 915-936.
[15] Xu-Xu Deng, Shan-Shan Li, Feng-Yan Sun. Necrostatin-1 Prevents Necroptosis in Brains after Ischemic Stroke via Inhibition of RIPK1-Mediated RIPK3/MLKL Signaling[J]. Aging and disease, 2019, 10(4): 807-817.
Full text



Copyright © 2014 Aging and Disease, All Rights Reserved.
Address: Aging and Disease Editorial Office 3400 Camp Bowie Boulevard Fort Worth, TX76106 USA
Fax: (817) 735-0408 E-mail:
Powered by Beijing Magtech Co. Ltd