Perineuronal Nets Degradation and Parvalbumin Interneuron Loss in a Mouse Model of DEPDC5-Related Epilepsy

Yang, Tao; Hu, Shuntong; Chang, Wei-Chih; Kao, Hsin-Yi; Wang, Yu

doi:10.1159/000525039

Cited by 7 publications

(14 citation statements)

References 22 publications

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“…Indeed, several review articles have summarized and discussed possible implications of PNNs for the pathophysiology of epilepsy ( McRae and Porter, 2012 ; Wen et al, 2018 ; Chaunsali et al, 2021 ). A recently published study generated a conditional knockout of Depdc5 , a gene highly involved in the target of rapamycin (mTOR) pathway and furthermore one of the most causative genes in patients with epilepsy and malformations of the cortex ( Yang et al, 2023 ). A loss of PNNs was observed, which was accompanied by a reduction in parvalbumin-expressing interneurons ( Yang et al, 2023 ).…”

Section: The Influence Of the Extracellular Matrix On Parvalbumin-exp...mentioning

confidence: 99%

“…A recently published study generated a conditional knockout of Depdc5 , a gene highly involved in the target of rapamycin (mTOR) pathway and furthermore one of the most causative genes in patients with epilepsy and malformations of the cortex ( Yang et al, 2023 ). A loss of PNNs was observed, which was accompanied by a reduction in parvalbumin-expressing interneurons ( Yang et al, 2023 ). Importantly, the authors could verify a microglia-induced proteolytic degradation of PNNs before the seizures occurred.…”

Section: The Influence Of the Extracellular Matrix On Parvalbumin-exp...mentioning

confidence: 99%

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Regulation of the E/I-balance by the neural matrisome

Mueller-Buehl

Wegrzyn

Bauch

et al. 2023

Front. Mol. Neurosci.

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In the mammalian cortex a proper excitatory/inhibitory (E/I) balance is fundamental for cognitive functions. Especially γ-aminobutyric acid (GABA)-releasing interneurons regulate the activity of excitatory projection neurons which form the second main class of neurons in the cortex. During development, the maturation of fast-spiking parvalbumin-expressing interneurons goes along with the formation of net-like structures covering their soma and proximal dendrites. These so-called perineuronal nets (PNNs) represent a specialized form of the extracellular matrix (ECM, also designated as matrisome) that stabilize structural synapses but prevent the formation of new connections. Consequently, PNNs are highly involved in the regulation of the synaptic balance. Previous studies revealed that the formation of perineuronal nets is accompanied by an establishment of mature neuronal circuits and by a closure of critical windows of synaptic plasticity. Furthermore, it has been shown that PNNs differentially impinge the integrity of excitatory and inhibitory synapses. In various neurological and neuropsychiatric disorders alterations of PNNs were described and aroused more attention in the last years. The following review gives an update about the role of PNNs for the maturation of parvalbumin-expressing interneurons and summarizes recent findings about the impact of PNNs in different neurological and neuropsychiatric disorders like schizophrenia or epilepsy. A targeted manipulation of PNNs might provide an interesting new possibility to indirectly modulate the synaptic balance and the E/I ratio in pathological conditions.

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Section: The Influence Of the Extracellular Matrix On Parvalbumin-exp...mentioning

confidence: 99%

Section: The Influence Of the Extracellular Matrix On Parvalbumin-exp...mentioning

confidence: 99%

Regulation of the E/I-balance by the neural matrisome

Mueller-Buehl

Wegrzyn

Bauch

et al. 2023

Front. Mol. Neurosci.

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“…Male homozygous floxed Depdc5 mice (Depdc5 F/F ) were bred with female mice heterozygous for floxed Depdc5 (Depdc5 F/W ) and heterozygous for the Cre allele to generate litters of homozygous CKO (Rbp4-Cre; Depdc5 F/F or Nkx2.1-Cre; Depdc5 F/F ), heterozygous CKO (Rbp4-Cre; Depdc5 F/W or Nkx2.1-Cre; Depdc5 F/W ), and wild-type (WT) (Depdc5 F/F or Depdc5 F/W ) mice. Because our pilot study showed that Rbp4-Cre; Dedpc5 F/W displayed no pathological or epileptic phenotypes, in addition to previous studies showing that Emx1-Cre; Depdc5 F/W and Syn1-Cre; Depdc5 F/W had no phenotypes, [16][17][18] Rbp4-Cre; Depdc5 F/W mice were also used as littermate controls. DNA was extracted from mouse tail biopsies using the Extract-N-Amp Tissue polymerase chain reaction (PCR) kit (Sigma; XNAT2-1KT) according to the manufacturer's instructions.…”

Section: Animalsmentioning

confidence: 99%

“…We and others have shown that Emx1-Cre mediated Depdc5 deletion in dorsal cortical progenitors causes severe epilepsy, megalencephaly, and premature death around postnatal (P) weeks 2 to 3. 16,17 Surprisingly, Syn1-Cre mediated Depdc5 deletion in all neuronal lineages (excitatory and inhibitory neurons) and neural structures often caused just one terminal seizure followed by death at 3 months old. 9,18 These striking phenotypic differences suggest that epileptogenesis and SUDEP in DEPDC5related epilepsy could be cell-type dependent.…”

Section: Depdc5 Deletion In a Subpopulation Of Forebrain Excitatory N...mentioning

confidence: 99%

“…These mice developed clusters of tonic-clonic seizures, status epilepticus, wasting, and malnutrition, making it difficult to determine the cause of death. 16,17 On the other hand, mice with a pan-neuronal knockout of Depdc5 died after a single terminal seizure at 3 months of age. 9,18 Interestingly, the majority of these mice had no history of seizures, representing an extremely rare patient event.…”

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Sudden Unexpected Death in Epilepsy and Respiratory Defects in a Mouse Model of DEPDC5‐Related Epilepsy

Kao,

Yao,

Yang

et al. 2023

Annals of Neurology

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ObjectivesDEPDC5 is a common causative gene in familial focal epilepsy with or without malformations of cortical development. Its pathogenic variants also confer a significantly higher risk for sudden unexpected death in epilepsy (SUDEP), providing opportunities to investigate the pathophysiology intersecting neurodevelopment, epilepsy, and cardiorespiratory function. There is an urgent need to gain a mechanistic understanding of DEPDC5‐related epilepsy and SUDEP, identify biomarkers for patients at high risk, and develop preventive interventions.MethodsDepdc5 was specifically deleted in excitatory or inhibitory neurons in the mouse brain to determine neuronal subtypes that drive epileptogenesis and SUDEP. EEG, cardiac, and respiratory recordings were performed to determine cardiorespiratory phenotypes associated with SUDEP. Baseline respiratory function and the response to hypoxia challenge were also studied in these mice.ResultsDepdc5 deletion in excitatory neurons in cortical layer 5 and dentate gyrus caused frequent generalized tonic–clonic seizures and SUDEP in young adult mice, but Depdc5 deletion in cortical interneurons did not. EEG suppression immediately following ictal offset was observed in fatal and non‐fatal seizures, but low amplitude rhythmic theta frequency activity was lost only in fatal seizures. In addition, these animals developed baseline respiratory dysfunction prior to SUDEP, during which ictal apnea occurred long before terminal cardiac asystole.InterpretationDepdc5 deletion in excitatory neurons is sufficient to cause DEPDC5‐related epilepsy and SUDEP. Ictal apnea and respiratory dysregulation play critical roles in SUDEP. Our study also provides a novel mouse model to investigate the underlying mechanisms of DEPDC5‐related epilepsy and SUDEP.This article is protected by copyright. All rights reserved.

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Increased expression of chondroitin sulfate proteoglycans in dentate gyrus and amygdala causes postinfectious seizures

Patel,

Swift,

Tewari

et al. 2023

Brain

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Alterations in the extracellular matrix (ECM) are common in patients with epilepsy and in animal models of epilepsy, yet whether they are cause or consequence of seizures and epilepsy development is unknown. Using Theiler’s murine encephalomyelitis virus (TMEV) infection-induced model of acquired epilepsy, we find de novo expression of chondroitin sulfate proteoglycans (CSPGs), a major ECM component, in dentate gyrus (DG) and amygdala exclusively in mice with acute seizures. Preventing synthesis of CSPGs specifically in DG and amygdala by deletion of the major CSPG aggrecan reduced seizure burden. Patch-clamp recordings from dentate granule cells (DGCs) revealed enhanced intrinsic and synaptic excitability in seizing mice that was significantly ameliorated by aggrecan deletion. In situ experiments suggest that DGCs hyperexcitability results from negatively charged CSPGs increasing stationary cations on the membrane thereby depolarizing neurons, increasing their intrinsic and synaptic excitability. These results show increased expression of CSPGs in the DG and amygdala as one of the causal factors for TMEV-induced acute seizures. We also show identical changes in CSPGs in pilocarpine-induced epilepsy suggesting that enhanced CSPGs in the DG and amygdala may be a common ictogenic factor and potential therapeutic target.

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Perineuronal Nets Degradation and Parvalbumin Interneuron Loss in a Mouse Model of DEPDC5-Related Epilepsy

Cited by 7 publications

References 22 publications

Regulation of the E/I-balance by the neural matrisome

Regulation of the E/I-balance by the neural matrisome

Sudden Unexpected Death in Epilepsy and Respiratory Defects in a Mouse Model of DEPDC5‐Related Epilepsy

Increased expression of chondroitin sulfate proteoglycans in dentate gyrus and amygdala causes postinfectious seizures

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