Role of Perineuronal Nets in Epilepsy
神经周围网在癫痫中的作用
基本信息
- 批准号:10516038
- 负责人:
- 金额:$ 37.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAcuteAffectAgglutininsAmino AcidsAstrocytesAxonBehaviorBindingBiophysicsBrainBuffersCell Differentiation processCellsChargeChronicClinicalCompensationDendritesDevelopmentDigestionDiseaseElectric CapacitanceElectrodesElectrostaticsEnsureEnzymesEpilepsyEpileptogenesisEquilibriumExcitatory SynapseExtracellular MatrixFire - disastersFrequenciesGeneticGlycoproteinsGlycosaminoglycansGolgi ApparatusGrantHealthHippocampusHomeostasisHyaluronidaseImmunohistochemistryImpairmentInfectionInjuryInterneuronsIonsLabelLesionMatrix MetalloproteinasesMediatingMembraneModelingMusMyelinNerve DegenerationNeuronsNeurotransmittersOutputParvalbuminsPatientsPeptide HydrolasesPersonsPharmaceutical PreparationsPhysiologicalPopulationProcessPropertyProteinsProteolysisRoleSeizuresSpeedStainsStrokeStructureSulfateSynapsesSyndromeTherapeuticTissuesVertebral columnWisteriaacquired epilepsyclinically relevantextracellulargamma-Aminobutyric Acidhuman tissueinhibitory neuronmouse modelnervous system disorderneuralneuronal cell bodyneurotransmissionnovelnovel strategiespatch clamppharmacologicpostsynapticpresynapticpreventpreventable epilepsyreceptorsugarsynaptic functiontherapeutic targettumoruptake
项目摘要
PROJECT SUMMARY/ABSTRACT
Approximately 50 million people worldwide live with epilepsy, a syndrome characterized by repeated,
unprovoked seizures that manifest with a combination of altered behavior and abnormal electric discharges of
populations of neurons in the brain. Seizures result from impairment of excitatory-inhibitory (E-I) balance.
Enhancement of inhibitory GABAergic function is a common pharmacological strategy. Not surprisingly,
GABAergic interneurons in the cortex and hippocampus have been well studied, and their role in dampening
excitatory output from these structures is well established. GABAergic interneurons tend to be fast-spiking cells
(up to 800Hz!), which compensate for their small number by a high level of activity with each action potential
causing GABA release from their terminals. A majority of these fast-spiking neurons are surrounded by a layer
of dense extracellular matrix that Golgi termed perineuronal nets (PNNs) over 120 years ago. These are
composed of glycosaminoglycanes, negatively charged glycoproteins formed from a superfamily of proteins that
cover the cell soma, proximal dendrites and axon initial segment. Their role is not well known but believed to aid
in cell differentiation, neural protection and cortical plasticity. During the last grant cycle studying tumor-
associated epilepsy, we made an unexpected discovery suggesting that PNNs alter the neuronal membrane
capacitance, allowing them to fire at supra-physiological rates. Specially, proteolytic enzymes released from the
tumor digest PNNs, thereby increasing membrane capacitance and slowing the firing rates of inhibitory neurons,
leading to seizures. We now hypothesize that PNNs may be more generally the target of acquired epilepsy,
where proteolysis of extracellular matrix and tissue remodeling are common. Hence, we propose to study PNN
integrity and its role in epileptogenesis more broadly across different mouse models of acquired epilepsy and in
tissues from epilepsy patients. We hypothesize that PNNs define the placement of astrocytes near synapses to
aid uptake of ions and neurotransmitters; that release of matrix-degrading enzymes from reactive astrocytes
destroy PNNs, thereby slowing their firing rate. Together these changes may lead to epilepsy. These studies are
conceptually novel and may suggest a completely different treatment approach to epilepsy, namely targeting
proteolytic enzymes to ameliorate this disease.
项目总结/文摘
项目成果
期刊论文数量(0)
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HARALD W SONTHEIMER其他文献
HARALD W SONTHEIMER的其他文献
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{{ truncateString('HARALD W SONTHEIMER', 18)}}的其他基金
Changes in Cerebrovascular Function with Aging in Normal and AD Brain
正常脑和 AD 脑中脑血管功能随衰老的变化
- 批准号:
10543141 - 财政年份:2020
- 资助金额:
$ 37.95万 - 项目类别:
Changes in Cerebrovascular Function with Aging in Normal and AD Brain
正常脑和 AD 脑中脑血管功能随衰老的变化
- 批准号:
10438950 - 财政年份:2020
- 资助金额:
$ 37.95万 - 项目类别:
Changes in Cerebrovascular Function with Aging in Normal and AD Brain
正常脑和 AD 脑中脑血管功能随衰老的变化
- 批准号:
10334548 - 财政年份:2020
- 资助金额:
$ 37.95万 - 项目类别:
Regulation of Amino-acid Transport in Human Gliomas
人类神经胶质瘤中氨基酸运输的调节
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10393364 - 财政年份:2018
- 资助金额:
$ 37.95万 - 项目类别:
Regulation of Amino-acid Transport in Human Gliomas
人类神经胶质瘤中氨基酸运输的调节
- 批准号:
10064133 - 财政年份:2018
- 资助金额:
$ 37.95万 - 项目类别:
Regulation of Amino-acid Transport in Human Gliomas
人类神经胶质瘤中氨基酸运输的调节
- 批准号:
10321925 - 财政年份:2018
- 资助金额:
$ 37.95万 - 项目类别:
Regulation of Amino-acid Transport in Human Gliomas
人类神经胶质瘤中氨基酸运输的调节
- 批准号:
10520044 - 财政年份:2018
- 资助金额:
$ 37.95万 - 项目类别:
Amino Acid Transport and the Biology of Human Gliomas
氨基酸转运和人类神经胶质瘤的生物学
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9131426 - 财政年份:2015
- 资助金额:
$ 37.95万 - 项目类别:
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