Circuit-based mechanisms of neuronal vulnerability in the adult EC
成人内皮细胞神经元脆弱性的基于回路的机制
基本信息
- 批准号:10400031
- 负责人:
- 金额:$ 4.68万
- 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:2021-04-15 至 2024-04-14
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAddressAdultAlzheimer&aposs DiseaseApoptosisApoptoticAutomobile DrivingAxonBindingBrainBrain regionCell DeathCellsCessation of lifeChloride ChannelsChronicCodeCognitive deficitsCommunicationCytoplasmic GranulesDataDevelopmentDevelopmental ProcessDiseaseElectrophysiology (science)EngineeringExcisionExhibitsFire - disastersFunctional disorderFutureGenerationsGeneticGliosisGlutamatesGlycineGoalsHippocampus (Brain)Infusion proceduresInjuryIvermectinLifeLigandsMediatingMemoryModelingMorphologic artifactsMusNerve DegenerationNeurodegenerative DisordersNeuronsNeurotransmittersPathway interactionsPatternPerforant PathwayPharmacologyPopulationProcessSignal TransductionSodium ChannelSymptomsSynapsesSynaptic plasticityTestingTetanus ToxinTetrodotoxinbasecompetitive environmentcritical perioddentate gyrusentorhinal cortexexperimental studygenetic approachgranule cellin vivoinsightmouse modelneuron lossneuronal survivalneurotransmitter releasepostnatalpostnatal developmentpostnatal periodpostsynapticpreventpro-apoptotic proteinresponseway finding
项目摘要
Project summary/abstract.
Entorhinal cortex layer II (ECII) neurons are some of the first cells to degenerate in Alzheimer’s Disease (AD). ECII
axons form the perforant pathway and are the major cortical input into the hippocampus. The perforant pathway supports
memory formation and spatial navigation throughout life, and loss of this input is consistent with the cognitive deficits
that present early in AD. To mimic the loss of this input in AD, the Jankowsky lab created a chemogenetic mouse model
of perforant pathway disruption in which a subset of ECII neurons express an engineered chloride channel (GlyCl) to
prevent the generation of action potentials. We unexpectedly discovered that entorhinal neurons were highly vulnerable to
silencing. Shortly after being inactivated, many ECII neurons retract their axons from the dentate gyrus, express pro-
apoptotic proteins, and then are eliminated from the circuit. We observed similar neurodegeneration after eliminating
neurotransmitter release with tetanus toxin (TeTX), confirming that neuronal loss is not an artifact of GlyCl activation.
Further, this silencing-induced degeneration is not shared by other brain regions, as neither the pre/parasubiculum nor
retrosplenial cortex exhibit cell loss after neuronal inactivation. This suggests that specific features of the entorhinal
cortex may confer neuronal vulnerability to inactivity. One possible vulnerability could be related to the formation of
entorhinal-hippocampal circuit. We noted that the pattern of ECII degeneration after silencing was strikingly similar to the
processes that guide to refinement of the perforant pathway during development. In early post-natal periods, inactive ECII
neurons are pruned from the circuit in a process that is mediated by local differences in activity, referred to as activity-
dependent competition. Projections are only pruned when neurons are sparsely inactive - when all cells are equally
inactive, none are removed. This proposal will test two hypotheses about the cellular mechanism driving neuronal death in
the mature entorhinal cortex. Aim 1 will determine whether activity-dependent competition persists in the adult ECII.
Pharmacological and genetic approaches will be used to modulate relative activity levels to determine how cell death is
influenced by activity differences between neighboring cells. Aim 2 will determine whether post-synaptic partners
promote the survival of ECII neurons. Our preliminary data suggests that eliminating neurotransmitter release from ECII
neurons – without blocking action potentials - is sufficient to induce degeneration. I will therefore use pharmacological
and genetic approaches to both reduce neurotransmitter binding in dentate granule cells and eliminate their ability to fire
action potentials in response to ECII input. This will test whether neurotransmitter-mediate signaling, or post-synaptic
activity itself, is required for ECII neuron survival. Data from these aims will determine how activity disruption may
mediate cell death in the adult brain. Further, these data may suggest that mechanisms which drive cell death during
postnatal development are not necessarily limited to critical periods but may persist into adulthood within certain
pathways. Understanding these mechanisms may inform future studies on neurodegenerative disease and how circuit
disruption may contribute to neuronal loss.
项目总结/抽象。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Caleb Wood其他文献
Caleb Wood的其他文献
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{{ truncateString('Caleb Wood', 18)}}的其他基金
Circuit-based mechanisms of neuronal vulnerability in the adult EC
成人内皮细胞神经元脆弱性的基于回路的机制
- 批准号:
10615015 - 财政年份:2021
- 资助金额:
$ 4.68万 - 项目类别:
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