Network-Related Changes in Neurotransmitters and Seizure Propagation During Rodent Epileptogenesis

Dhaher, Roni; Gruenbaum, Shaun E.; Sandhu, Mani Ratnesh S.; Ottestad-Hansen, Sigrid; Tu, Nathan; Wang, Yue; Lee, Tih‐Shih W.; Deshpande, Ketaki; Spencer, Dennis D.; Danbolt, Niels Christian; Zaveri, Hitten P.; Eid, Tore

doi:10.1212/wnl.0000000000011846

Cited by 14 publications

(9 citation statements)

References 50 publications

(85 reference statements)

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“… 2 Microdialysis studies reveal that the extracellular concentration of glutamate is indeed elevated both before and during seizure onset, suggesting that enhanced glutamate release and/or impaired uptake may occur in epilepsy. 3 , 4 It is well known that following a variety of brain insults including injury, infections, and acute seizures, astrocytes become “reactive,” changing their morphology, protein expression, and function. In line with elevated glutamate signaling in the epileptic brain, GLT-1 levels can be decreased in “reactive” astrocytes which would lead to elevated glutamate levels.…”

Section: Commentarymentioning

confidence: 99%

Oops!...Glutamate Did it Again

J¹,

Dulla²

2021

Epilepsy Curr

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Increasing astrocyte glutamate uptake is protective in a model of epilepsy Peterson, Allison R., et al. Targeted overexpression of glutamate transporter-1 reduces seizures and attenuates pathological changes in a mouse model of epilepsy. Neurobiology of Disease, 2021. P157.Astrocytic glutamate transporters are crucial for glutamate homeostasis in the brain, and dysregulation of these transporters can contribute to the development of epilepsy. Glutamate transporter-1 (GLT-1) is responsible for the majority of glutamate uptake in the dorsal forebrain and has been shown to be reduced at epileptic foci in patients and preclinical models of temporal lobe epilepsy (TLE). Current antiepileptic drugs (AEDs) work primarily by targeting neurons directly through suppression of excitatory neurotransmission or enhancement of inhibitory neurotransmission, which can lead to both behavioral and psychiatric side effects. This study investigates the therapeutic capacity of astrocyte-specific AAV-mediated GLT-1 expression in the intrahippocampal kainic acid (IHKA) model of TLE. In this study, we used Western blot analysis, immunohistochemistry, and long-term-video EEG monitoring to demonstrate that cell-type-specific upregulation of GLT-1 in astrocytes is neuroprotective at early time points during epileptogenesis, reduces seizure frequency and total time spent in seizures, and eliminates large behavioral seizures in the IHKA model of epilepsy. Our findings suggest that targeting glutamate uptake is a promising therapeutic strategy for the treatment of epilepsy.

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Section: Commentarymentioning

confidence: 99%

Oops!...Glutamate Did it Again

J¹,

Dulla²

2021

Epilepsy Curr

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“…Glutamate is a well-known excitatory neurotransmitter and its accumulation in the brain is a contributing factor for seizure generation [ 37 ]. Moreover, our prior work confirmed that glutamate by the concentration of 5 mM for 8 h was sufficient for triggering ferroptosis in HT22 cells [ 12 , 25 ].…”

Section: Resultsmentioning

confidence: 99%

D-Penicillamine Reveals the Amelioration of Seizure-Induced Neuronal Injury via Inhibiting Aqp11-Dependent Ferroptosis

et al. 2022

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Repetitive seizures, a common phenomenon in diverse neurologic conditions such as epilepsy, can undoubtedly cause neuronal injury and our prior work reveals that ferroptosis is a contributing factor of neuronal damage post seizure. However, there is no drug available in clinical practice for ameliorating seizure-induced neuronal impairment via targeting ferroptosis. Our present work aimed to explore whether D-penicillamine (DPA), an originally approved drug for treating Wilson’s disease, inhibited neuronal ferroptosis and alleviated seizure-associated brain damage. Our findings revealed that DPA remarkably improved neuronal survival in kainic acid (KA)-treated mouse model. Furthermore, ferroptosis-associated indices including acyl-coA synthetase long chain family member 4 (ACSL4), prostaglandin-endoperoxide synthase 2 (Ptgs2) gene and lipid peroxide (LPO) level were significantly decreased in KA mouse model after DPA treatment. In a ferroptotic cell death model induced by glutamate or erastin, DPA was also validated to evidently suppress neuronal ferroptosis. The results from RNA-seq analysis indicated that Aqp11, a gene coding previously reported channel protein responsible for transporting water and small solutes, was identified as a molecular target by which DPA exerted anti-ferroptotic potential in neurons. The experimental results from in vivo Aqp11 siRNA transfer into the brain also confirmed that knockdown of Aqp11 abrogated the inhibitory effect of seizure-induced ferroptosis after DPA treatment, suggesting that the effects of DPA on ferroptosis process are dependent upon Aqp11. In conclusion, DPA can be repurposed to cure seizure disorders such as epilepsy.

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“…Besides, poorly controlled SE is one of the highest risk factors for chronic epileptogenesis ( Tong et al, 2022 ). Repetitive propagation of TLE seizures leads to additional brain damages in brain regions outside of initial focus which give rise to secondary epileptogenesis and comorbidities ( Dhaher et al, 2021 ). Thus, interfering with the NAc shell neurons of the TLE brain may not only confine acute seizure severity, but also may limit the development of drug-resistant epileptogenesis and related neurological comorbidities at the post-SE stages.…”

Section: Discussionmentioning

confidence: 99%

Nucleus accumbens shell modulates seizure propagation in a mouse temporal lobe epilepsy model

Zou

Guo

Suo

et al. 2022

Front. Cell Dev. Biol.

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Temporal lobe epilepsy (TLE) is the most common form of epilepsy with focal seizures which in some conditions can develop into secondarily generalized tonic–clonic seizures by the propagation of epileptic activities in the temporal lobe to other brain areas. The nucleus accumbens (NAc) has been suggested as a treatment target for TLE as accumulating evidence indicates that the NAc, especially its shell, participates in the process of epileptic seizures of patients and animal models with TLE. The majority of neurons in the NAc are GABAergic medium spiny neurons (MSNs) expressing dopamine receptor D1 (D1R) or dopamine receptor D2 (D2R). However, the direct evidence of the NAc shell participating in the propagation of TLE seizures is missing, and its cell type-specific modulatory roles in TLE seizures are unknown. In this study, we microinjected kainic acid into basolateral amygdala (BLA) to make a mouse model of TLE with initial focal seizures and secondarily generalized seizures (SGSs). We found that TLE seizures caused robust c-fos expression in the NAc shell and increased neuronal excitability of D1R-expressing MSN (D1R-MSN) and D2R-expressing MSN (D2R-MSN). Pharmacological inhibition of the NAc shell alleviated TLE seizures by reducing the number of SGSs and seizure stages. Cell-type-specific chemogenetic inhibition of either D1R-MSN or D2R-MSN showed similar effects with pharmacological inhibition of the NAc shell. Both pharmacological and cell-type-specific chemogenetic inhibition of the NAc shell did not alter the onset time of focal seizures. Collectively, these findings indicate that the NAc shell and its D1R-MSN or D2R-MSN mainly participate in the propagation and generalization of the TLE seizures.

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Network-Related Changes in Neurotransmitters and Seizure Propagation During Rodent Epileptogenesis

Cited by 14 publications

References 50 publications

Oops!...Glutamate Did it Again

Oops!...Glutamate Did it Again

D-Penicillamine Reveals the Amelioration of Seizure-Induced Neuronal Injury via Inhibiting Aqp11-Dependent Ferroptosis

Nucleus accumbens shell modulates seizure propagation in a mouse temporal lobe epilepsy model

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