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Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline.

Cho KO, Lybrand ZR, Ito N, Brulet R, Tafacory F, Zhang L, Good L, Ure K, Kernie SG, Birnbaum SG, Scharfman HE, Eisch AJ, Hsieh J - Nat Commun (2015)

Bottom Line: Acute seizures after a severe brain insult can often lead to epilepsy and cognitive impairment.Aberrant hippocampal neurogenesis follows the insult but the role of adult-generated neurons in the development of chronic seizures or associated cognitive deficits remains to be determined.These findings establish a key role of neurogenesis in chronic seizure development and associated memory impairment and suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Pharmacology, School of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.

ABSTRACT
Acute seizures after a severe brain insult can often lead to epilepsy and cognitive impairment. Aberrant hippocampal neurogenesis follows the insult but the role of adult-generated neurons in the development of chronic seizures or associated cognitive deficits remains to be determined. Here we show that the ablation of adult neurogenesis before pilocarpine-induced acute seizures in mice leads to a reduction in chronic seizure frequency. We also show that ablation of neurogenesis normalizes epilepsy-associated cognitive deficits. Remarkably, the effect of ablating adult neurogenesis before acute seizures is long lasting as it suppresses chronic seizure frequency for nearly 1 year. These findings establish a key role of neurogenesis in chronic seizure development and associated memory impairment and suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult.

No MeSH data available.


Related in: MedlinePlus

Seizures persist after near-complete ablation of neurogenesis.(a) Experimental design. (b) Microscopic images from three experiments showing DCX immunoreactivity at 6 weeks after pilocarpine (Pilo) injection. Scale bar, 200 μm. Inset shows typical DCX-positive cells in epilepsy. Scale bar, 20 μm. (c) Graphs showing the number of DCX-expressing cells in subgranular zone (SGZ) and the hilus in Veh/Pilo/Veh (n=11) and GCV/Pilo/GCV group (n=12). Mann–Whitney U-test, P<0.001, U=3.000 for the left graph; Mann–Whitney U-test, P<0.001, U=8.000 for the right graph. (d) Microscopic images from three experiments showing the dentate gyrus stained with Prox1, a marker for granule neurons. Scale bar, 100 μm. Inset shows typical EGCs in epilepsy. Scale bar, 20 μm. (e) A graph showing the number of EGCs in the hilus of Veh/Pilo/Veh (n=11) and GCV/Pilo/GCV group (n=12). Mann–Whitney U-test, P<0.001, U=8.000. (f) Experimental design. (g) Graphs showing SRS frequency and duration between Veh/Pilo/Veh (n=24) and GCV/Pilo/GCV groups (n=22). Mann–Whitney U-test, P=0.092, U=187.500 for the left graph; Student’s t-test, P=0.404, t(41)=−0.843 for the right graph. (h) Experimental design. (i) Confocal images from three experiments showing representative Nestin-TK GFP/GFAP/BrdU- (arrows) and GFAP/BrdU-immunoreactive cells (arrowheads) in the hilus. Scale bar, 20 μm. (j) Graphs showing the number of proliferating reactive astrocytes expressing Nestin-TK GFP, examined by Nestin-TK GFP/GFAP/BrdU+ cells and proliferating astrocytes not expressing Nestin-TK GFP, labelled as GFAP/BrdU staining, between Veh/Pilo/Veh (n=5) and GCV/Pilo/GCV group (n=6). Student’s t-test, P=0.049, t(9)=2.281 for the left graph; Student’s t-test, P=0.270, t(9)=1.174 for the right graph. Data presented as mean±s.e.m. *P<0.05. NS, not significant.
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f6: Seizures persist after near-complete ablation of neurogenesis.(a) Experimental design. (b) Microscopic images from three experiments showing DCX immunoreactivity at 6 weeks after pilocarpine (Pilo) injection. Scale bar, 200 μm. Inset shows typical DCX-positive cells in epilepsy. Scale bar, 20 μm. (c) Graphs showing the number of DCX-expressing cells in subgranular zone (SGZ) and the hilus in Veh/Pilo/Veh (n=11) and GCV/Pilo/GCV group (n=12). Mann–Whitney U-test, P<0.001, U=3.000 for the left graph; Mann–Whitney U-test, P<0.001, U=8.000 for the right graph. (d) Microscopic images from three experiments showing the dentate gyrus stained with Prox1, a marker for granule neurons. Scale bar, 100 μm. Inset shows typical EGCs in epilepsy. Scale bar, 20 μm. (e) A graph showing the number of EGCs in the hilus of Veh/Pilo/Veh (n=11) and GCV/Pilo/GCV group (n=12). Mann–Whitney U-test, P<0.001, U=8.000. (f) Experimental design. (g) Graphs showing SRS frequency and duration between Veh/Pilo/Veh (n=24) and GCV/Pilo/GCV groups (n=22). Mann–Whitney U-test, P=0.092, U=187.500 for the left graph; Student’s t-test, P=0.404, t(41)=−0.843 for the right graph. (h) Experimental design. (i) Confocal images from three experiments showing representative Nestin-TK GFP/GFAP/BrdU- (arrows) and GFAP/BrdU-immunoreactive cells (arrowheads) in the hilus. Scale bar, 20 μm. (j) Graphs showing the number of proliferating reactive astrocytes expressing Nestin-TK GFP, examined by Nestin-TK GFP/GFAP/BrdU+ cells and proliferating astrocytes not expressing Nestin-TK GFP, labelled as GFAP/BrdU staining, between Veh/Pilo/Veh (n=5) and GCV/Pilo/GCV group (n=6). Student’s t-test, P=0.049, t(9)=2.281 for the left graph; Student’s t-test, P=0.270, t(9)=1.174 for the right graph. Data presented as mean±s.e.m. *P<0.05. NS, not significant.

Mentions: The reason why ablation of neurogenesis before acute seizures only reduced chronic seizure frequency, but did not completely prevent epilepsy, could be explained by neurons generated after seizures or other factors. To discriminate between these two possibilities, we treated Nestin-TK mice with GCV before and after pilocarpine to achieve near-complete ablation of neurogenesis (Fig. 6a). We found that after two rounds of GCV treatment (GCV/Pilo/GCV), DCX-expressing cells in the subgranular dentate gyrus and the hilus were fewer, compared with the group with no ablation of neurogenesis (Veh/Pilo/Veh; Fig. 6b,c). Furthermore, we found that Prox1-expressing hilar EGCs were significantly decreased in GCV/Pilo/GCV group (Fig. 6d,e). However, MFS stained by zinc transporter-3 still did not significantly differ between Veh/Pilo and GCV/Pilo groups, similar to ablation of neurogenesis before acute seizures (Supplementary Fig. 4). Unexpectedly, we found no significant difference in chronic seizures between the Veh/Pilo/Veh and GCV/Pilo/GCV groups, although there was a decreasing trend in the SRS frequency in the GCV/Pilo/GCV group (Fig. 6f,g).


Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline.

Cho KO, Lybrand ZR, Ito N, Brulet R, Tafacory F, Zhang L, Good L, Ure K, Kernie SG, Birnbaum SG, Scharfman HE, Eisch AJ, Hsieh J - Nat Commun (2015)

Seizures persist after near-complete ablation of neurogenesis.(a) Experimental design. (b) Microscopic images from three experiments showing DCX immunoreactivity at 6 weeks after pilocarpine (Pilo) injection. Scale bar, 200 μm. Inset shows typical DCX-positive cells in epilepsy. Scale bar, 20 μm. (c) Graphs showing the number of DCX-expressing cells in subgranular zone (SGZ) and the hilus in Veh/Pilo/Veh (n=11) and GCV/Pilo/GCV group (n=12). Mann–Whitney U-test, P<0.001, U=3.000 for the left graph; Mann–Whitney U-test, P<0.001, U=8.000 for the right graph. (d) Microscopic images from three experiments showing the dentate gyrus stained with Prox1, a marker for granule neurons. Scale bar, 100 μm. Inset shows typical EGCs in epilepsy. Scale bar, 20 μm. (e) A graph showing the number of EGCs in the hilus of Veh/Pilo/Veh (n=11) and GCV/Pilo/GCV group (n=12). Mann–Whitney U-test, P<0.001, U=8.000. (f) Experimental design. (g) Graphs showing SRS frequency and duration between Veh/Pilo/Veh (n=24) and GCV/Pilo/GCV groups (n=22). Mann–Whitney U-test, P=0.092, U=187.500 for the left graph; Student’s t-test, P=0.404, t(41)=−0.843 for the right graph. (h) Experimental design. (i) Confocal images from three experiments showing representative Nestin-TK GFP/GFAP/BrdU- (arrows) and GFAP/BrdU-immunoreactive cells (arrowheads) in the hilus. Scale bar, 20 μm. (j) Graphs showing the number of proliferating reactive astrocytes expressing Nestin-TK GFP, examined by Nestin-TK GFP/GFAP/BrdU+ cells and proliferating astrocytes not expressing Nestin-TK GFP, labelled as GFAP/BrdU staining, between Veh/Pilo/Veh (n=5) and GCV/Pilo/GCV group (n=6). Student’s t-test, P=0.049, t(9)=2.281 for the left graph; Student’s t-test, P=0.270, t(9)=1.174 for the right graph. Data presented as mean±s.e.m. *P<0.05. NS, not significant.
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f6: Seizures persist after near-complete ablation of neurogenesis.(a) Experimental design. (b) Microscopic images from three experiments showing DCX immunoreactivity at 6 weeks after pilocarpine (Pilo) injection. Scale bar, 200 μm. Inset shows typical DCX-positive cells in epilepsy. Scale bar, 20 μm. (c) Graphs showing the number of DCX-expressing cells in subgranular zone (SGZ) and the hilus in Veh/Pilo/Veh (n=11) and GCV/Pilo/GCV group (n=12). Mann–Whitney U-test, P<0.001, U=3.000 for the left graph; Mann–Whitney U-test, P<0.001, U=8.000 for the right graph. (d) Microscopic images from three experiments showing the dentate gyrus stained with Prox1, a marker for granule neurons. Scale bar, 100 μm. Inset shows typical EGCs in epilepsy. Scale bar, 20 μm. (e) A graph showing the number of EGCs in the hilus of Veh/Pilo/Veh (n=11) and GCV/Pilo/GCV group (n=12). Mann–Whitney U-test, P<0.001, U=8.000. (f) Experimental design. (g) Graphs showing SRS frequency and duration between Veh/Pilo/Veh (n=24) and GCV/Pilo/GCV groups (n=22). Mann–Whitney U-test, P=0.092, U=187.500 for the left graph; Student’s t-test, P=0.404, t(41)=−0.843 for the right graph. (h) Experimental design. (i) Confocal images from three experiments showing representative Nestin-TK GFP/GFAP/BrdU- (arrows) and GFAP/BrdU-immunoreactive cells (arrowheads) in the hilus. Scale bar, 20 μm. (j) Graphs showing the number of proliferating reactive astrocytes expressing Nestin-TK GFP, examined by Nestin-TK GFP/GFAP/BrdU+ cells and proliferating astrocytes not expressing Nestin-TK GFP, labelled as GFAP/BrdU staining, between Veh/Pilo/Veh (n=5) and GCV/Pilo/GCV group (n=6). Student’s t-test, P=0.049, t(9)=2.281 for the left graph; Student’s t-test, P=0.270, t(9)=1.174 for the right graph. Data presented as mean±s.e.m. *P<0.05. NS, not significant.
Mentions: The reason why ablation of neurogenesis before acute seizures only reduced chronic seizure frequency, but did not completely prevent epilepsy, could be explained by neurons generated after seizures or other factors. To discriminate between these two possibilities, we treated Nestin-TK mice with GCV before and after pilocarpine to achieve near-complete ablation of neurogenesis (Fig. 6a). We found that after two rounds of GCV treatment (GCV/Pilo/GCV), DCX-expressing cells in the subgranular dentate gyrus and the hilus were fewer, compared with the group with no ablation of neurogenesis (Veh/Pilo/Veh; Fig. 6b,c). Furthermore, we found that Prox1-expressing hilar EGCs were significantly decreased in GCV/Pilo/GCV group (Fig. 6d,e). However, MFS stained by zinc transporter-3 still did not significantly differ between Veh/Pilo and GCV/Pilo groups, similar to ablation of neurogenesis before acute seizures (Supplementary Fig. 4). Unexpectedly, we found no significant difference in chronic seizures between the Veh/Pilo/Veh and GCV/Pilo/GCV groups, although there was a decreasing trend in the SRS frequency in the GCV/Pilo/GCV group (Fig. 6f,g).

Bottom Line: Acute seizures after a severe brain insult can often lead to epilepsy and cognitive impairment.Aberrant hippocampal neurogenesis follows the insult but the role of adult-generated neurons in the development of chronic seizures or associated cognitive deficits remains to be determined.These findings establish a key role of neurogenesis in chronic seizure development and associated memory impairment and suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Pharmacology, School of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.

ABSTRACT
Acute seizures after a severe brain insult can often lead to epilepsy and cognitive impairment. Aberrant hippocampal neurogenesis follows the insult but the role of adult-generated neurons in the development of chronic seizures or associated cognitive deficits remains to be determined. Here we show that the ablation of adult neurogenesis before pilocarpine-induced acute seizures in mice leads to a reduction in chronic seizure frequency. We also show that ablation of neurogenesis normalizes epilepsy-associated cognitive deficits. Remarkably, the effect of ablating adult neurogenesis before acute seizures is long lasting as it suppresses chronic seizure frequency for nearly 1 year. These findings establish a key role of neurogenesis in chronic seizure development and associated memory impairment and suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult.

No MeSH data available.


Related in: MedlinePlus