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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

Ablation of neurogenesis reduces spontaneous seizures.(a) Time line showing the experimental design. (b) Two subdural screws and two bipolar hippocampal in-depth electrodes were implanted to record EEG. LF, left frontal screw; LH, left hippocampal depth electrode; RH, right hippocampal depth electrode; RO, right occipital screw. (c) Video/EEG monitoring was performed on a freely moving mouse with a tethered system. (d) A representative Nissl image from four independent experiments showing a hippocampal electrode track (arrows). Scale bar, 500 μm. (e) A representative EEG trace from eight independent experiments showing generalized seizure activity. Details are presented as initial (1), middle (2) and end sections (3). (f) Graphs showing the frequency and duration of SRS of GCV-treated mice (n=18) and Veh-treated mice (n=15). Student’s t-test, P=0.037, t(31)=2.185 for the left graph; Student’s t-test, P=0.875, t(31)=−0.159 for the right graph. Data presented as mean±s.e.m. *P<0.05. NS, not significant.
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f2: Ablation of neurogenesis reduces spontaneous seizures.(a) Time line showing the experimental design. (b) Two subdural screws and two bipolar hippocampal in-depth electrodes were implanted to record EEG. LF, left frontal screw; LH, left hippocampal depth electrode; RH, right hippocampal depth electrode; RO, right occipital screw. (c) Video/EEG monitoring was performed on a freely moving mouse with a tethered system. (d) A representative Nissl image from four independent experiments showing a hippocampal electrode track (arrows). Scale bar, 500 μm. (e) A representative EEG trace from eight independent experiments showing generalized seizure activity. Details are presented as initial (1), middle (2) and end sections (3). (f) Graphs showing the frequency and duration of SRS of GCV-treated mice (n=18) and Veh-treated mice (n=15). Student’s t-test, P=0.037, t(31)=2.185 for the left graph; Student’s t-test, P=0.875, t(31)=−0.159 for the right graph. Data presented as mean±s.e.m. *P<0.05. NS, not significant.

Mentions: To examine the role of aberrant hippocampal neurogenesis in epilepsy, Nestin-TK mice were treated with Veh or GCV for 4 weeks, at which point they were injected with pilocarpine to establish chronic epilepsy (Fig. 2a). We then assessed the functional impact of ablation of neurogenesis on SRS 5 weeks after pilocarpine using continuous video/electroencephalogram (EEG) monitoring for 2 weeks. Two cortical epidural and two hippocampal depth electrodes were implanted 4 weeks after acute seizures and the number of generalized seizures, defined as simultaneous seizure activity in all four channels, was determined for 2 weeks in freely moving mice (Fig. 2b–e). Ablation of neurogenesis resulted in an ~40% reduction in SRS frequency, although SRS duration for each seizure was unaffected (Fig. 2f), suggesting that neurons born before acute seizure activity contribute to the development of recurrent seizures, but are not essential for epilepsy development.


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)

Ablation of neurogenesis reduces spontaneous seizures.(a) Time line showing the experimental design. (b) Two subdural screws and two bipolar hippocampal in-depth electrodes were implanted to record EEG. LF, left frontal screw; LH, left hippocampal depth electrode; RH, right hippocampal depth electrode; RO, right occipital screw. (c) Video/EEG monitoring was performed on a freely moving mouse with a tethered system. (d) A representative Nissl image from four independent experiments showing a hippocampal electrode track (arrows). Scale bar, 500 μm. (e) A representative EEG trace from eight independent experiments showing generalized seizure activity. Details are presented as initial (1), middle (2) and end sections (3). (f) Graphs showing the frequency and duration of SRS of GCV-treated mice (n=18) and Veh-treated mice (n=15). Student’s t-test, P=0.037, t(31)=2.185 for the left graph; Student’s t-test, P=0.875, t(31)=−0.159 for the right graph. Data presented as mean±s.e.m. *P<0.05. NS, not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4375780&req=5

f2: Ablation of neurogenesis reduces spontaneous seizures.(a) Time line showing the experimental design. (b) Two subdural screws and two bipolar hippocampal in-depth electrodes were implanted to record EEG. LF, left frontal screw; LH, left hippocampal depth electrode; RH, right hippocampal depth electrode; RO, right occipital screw. (c) Video/EEG monitoring was performed on a freely moving mouse with a tethered system. (d) A representative Nissl image from four independent experiments showing a hippocampal electrode track (arrows). Scale bar, 500 μm. (e) A representative EEG trace from eight independent experiments showing generalized seizure activity. Details are presented as initial (1), middle (2) and end sections (3). (f) Graphs showing the frequency and duration of SRS of GCV-treated mice (n=18) and Veh-treated mice (n=15). Student’s t-test, P=0.037, t(31)=2.185 for the left graph; Student’s t-test, P=0.875, t(31)=−0.159 for the right graph. Data presented as mean±s.e.m. *P<0.05. NS, not significant.
Mentions: To examine the role of aberrant hippocampal neurogenesis in epilepsy, Nestin-TK mice were treated with Veh or GCV for 4 weeks, at which point they were injected with pilocarpine to establish chronic epilepsy (Fig. 2a). We then assessed the functional impact of ablation of neurogenesis on SRS 5 weeks after pilocarpine using continuous video/electroencephalogram (EEG) monitoring for 2 weeks. Two cortical epidural and two hippocampal depth electrodes were implanted 4 weeks after acute seizures and the number of generalized seizures, defined as simultaneous seizure activity in all four channels, was determined for 2 weeks in freely moving mice (Fig. 2b–e). Ablation of neurogenesis resulted in an ~40% reduction in SRS frequency, although SRS duration for each seizure was unaffected (Fig. 2f), suggesting that neurons born before acute seizure activity contribute to the development of recurrent seizures, but are not essential for epilepsy development.

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