Early Seizure Activity Accelerates Depletion of Hippocampal Neural Stem Cells and Impairs Spatial Discrimination in an Alzheimer’s Disease Model

Fu, Chia-Hsuan; Iascone, Daniel Maxim; Petrof, Iraklis; Hazra, Anupam; Zhang, Xiaohong; Pyfer, Mark S.; Tosi, Umberto; Corbett, Brian; Cai, Jingli; Lee, Jason; Park, Jin; Iacovitti, Lorraine; Scharfman, Helen E.; Enikolopov, Grigori; Chin, Jeannie

doi:10.1016/j.celrep.2019.05.101

Cited by 60 publications

(68 citation statements)

References 107 publications

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“…The activation of adult NSCs transiently increases the number of new neurons but ultimately leads to the depletion of NSCs, indicating that the supply of new neurons is limited [69,70]. This mechanism has also been proposed in epilepsy models [71]. In epileptic seizures, abnormal firing stimulates NSCs, temporarily increasing the division of NSCs and promoting neurogenesis.…”

Section: Challenges Of Regenerative Therapy Involving the Activation mentioning

confidence: 93%

Current understanding of adult neurogenesis in the mammalian brain: how does adult neurogenesis decrease with age?

Kase

Shimazaki

2020

Inflamm Regener

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Adult neurogenesis occurs throughout life in restricted brain regions in mammals. However, the number of neural stem cells (NSCs) that generate new neurons steadily decreases with age, resulting in a decrease in neurogenesis. Transplantation of mesenchymal cells or cultured NSCs has been studied as a promising treatment in models of several brain injuries including cerebral infarction and cerebral contusion. Considering the problems of host-versusgraft reactions and the tumorigenicity of transplanted cells, the mobilization of endogenous adult NSCs should be more feasible for the treatment of these brain injuries. However, the number of adult NSCs in the adult brain is limited, and their mitotic potential is low. Here, we outline what we know to date about why the number of NSCs and adult neurogenesis decrease with age. We also discuss issues applicable to regenerative medicine.

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Section: Challenges Of Regenerative Therapy Involving the Activation mentioning

confidence: 93%

Current understanding of adult neurogenesis in the mammalian brain: how does adult neurogenesis decrease with age?

Kase

Shimazaki

2020

Inflamm Regener

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“…Early-onset epileptic activity in 1-and 2-month-old hAPP-J20 mice. Reproduced with permission from (Fu et al 2019).…”

Section: Fig2 Early-onset Neuronal Network Hyperexcitability In Hapmentioning

confidence: 99%

Neuronal Network Excitability in Alzheimer’s Disease: The Puzzle of Similar versus Divergent Roles of Amyloid β and Tau

Kazim

Seo

Bianchi

et al. 2021

eNeuro

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“…FosB can recruit histone-modifying proteins to target genes, a process that has been well-characterized in the nucleus accumbens (NAc), in which FosB accumulates after chronic exposure to drugs of abuse and regulates gene expression (Renthal et al, 2008;Robison and Nestler, 2011;Nestler and Luscher, 2019). Our work demonstrated that seizures induce FosB accumulation in the hippocampus of two mouse models with spontaneous recurrent seizures: pilocarpine-treated mice (Pilo mice) as well as transgenic mice that express human amyloid precursor protein (APP) carrying mutations linked to AD (line J20) (Corbett et al, 2017;You et al, 2017;Fu et al, 2019). Importantly, we showed that FosB also accumulates in the hippocampus of patients with AD and in patients with temporal lobe epilepsy (TLE) (You et al, 2017).…”

Section: Introductionmentioning

confidence: 79%

Genes Bound by ΔFosB in Different Conditions With Recurrent Seizures Regulate Similar Neuronal Functions

Stephens

Romain

et al. 2020

Front. Neurosci.

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Seizure incidence is increased in Alzheimer's disease (AD) patients and mouse models, and treatment with the antiseizure drug levetiracetam improves cognition. We reported that one mechanism by which seizures can exert persistent effects on cognition is through accumulation of FosB, a transcription factor with a long half-life. Even the infrequent seizures that spontaneously occur in transgenic mice expressing human amyloid precursor protein (APP) lead to persistent increases in FosB in the hippocampus, similar to what we observed in patients with AD or temporal lobe epilepsy. FosB epigenetically regulates expression of target genes, however, whether FosB targets the same genes when induced by seizures in different neurological conditions is not clear. We performed ChIP-sequencing to assess the repertoire of FosB target genes in APP mice and in pilocarpine-treated wildtype mice (Pilo mice), a pharmacological model of epilepsy. These mouse models allowed us to compare AD, in which seizures occur in the context of high levels of amyloid beta, and epilepsy, in which recurrent seizures occur without AD-specific pathophysiology. Network profiling of genes bound by FosB in APP mice, Pilo mice, and respective control mice revealed that functional domains modulated by FosB in the hippocampus are expanded and diversified in APP and Pilo mice (vs. respective controls). Domains of interest in both disease contexts involved neuronal excitability and neurotransmission, neurogenesis, chromatin remodeling, and cellular stress and neuroinflammation. To assess the gene targets bound by FosB regardless of seizure etiology, we focused on 442 genes with significant FosB binding in both APP and Pilo mice (vs. respective controls). Functional analyses identified pathways that regulate membrane potential, glutamatergic signaling, calcium homeostasis, complement activation, neuron-glia population maintenance, and chromatin dynamics. RNA-sequencing and qPCR measurements in independent mice detected altered expression of several FosB targets shared in APP and Pilo mice. Our findings indicate that seizure-induced FosB can bind genes in patterns that depend on seizure etiology, but can bind other genes regardless of seizure etiology. Understanding

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Early Seizure Activity Accelerates Depletion of Hippocampal Neural Stem Cells and Impairs Spatial Discrimination in an Alzheimer’s Disease Model

Cited by 60 publications

References 107 publications

Current understanding of adult neurogenesis in the mammalian brain: how does adult neurogenesis decrease with age?

Current understanding of adult neurogenesis in the mammalian brain: how does adult neurogenesis decrease with age?

Neuronal Network Excitability in Alzheimer’s Disease: The Puzzle of Similar versus Divergent Roles of Amyloid β and Tau

Genes Bound by ΔFosB in Different Conditions With Recurrent Seizures Regulate Similar Neuronal Functions

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