PROJECT 3-Synaptic function in behaviorally-characterized aged rats in circuits of the entorhinal cortex and dentate gyrus

项目 3-行为特征老年大鼠内嗅皮层和齿状回回路中的突触功能

• 批准号: 10412004
• 负责人: Alfredo Kirkwood
• 金额: $ 45.86万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412004
• 关键词: AMPA Receptors; Abeta synthesis; Ablation; Adult; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Area; Behavioral; Brain; Brain region; Cells; Cerebrospinal Fluid; Cognition; Cognitive; Cognitive aging; Data; Deposition; Dominant-Negative Mutation; Elderly; Equilibrium; Extracellular Protein; Functional disorder; Genetic; Hippocampus (Brain); Human; Hyperactivity; Impaired cognition; Impairment; Individual; Interneurons; Intervention; Lateral; Learning; Medial; Mediating; Memory; Memory impairment; Modeling; Mus; Neurons; Output; Parvalbumins; Pathogenicity; Pathway interactions; Performance; Phase; Play; Process; Production; Pyramidal Cells; Rattus; Regulation; Research; Rodent; Rodent Model; Role; Sensory; Simian virus 40; Structure; Synapses; System; Targeted Research; Temporal Lobe; Testing; Theoretical Studies; Toxic effect; Transfection; Viral; Virus; Whole-Cell Recordings; age related; aged; base; calmodulin-dependent protein kinase II; cell age; cognitive function; cognitive performance; comparative; dentate gyrus; entorhinal cortex; excitatory neuron; experience; experimental study; functional status; mossy fiber; neuronal pentraxin; novel; optogenetics; overexpression; postsynaptic; preservation; programs; recruit; relating to nervous system; sensory cortex; synaptic function; tau Proteins; therapeutic target

Aging frequently impairs cognitive functions associated with the medial temporal lobe (MTL), particularly the formation of new memories, and it is also a major risk factor for Alzheimer’s disease (AD). Recent studies in rodent models and humans identified hyperactivity in specific circuits/subregions of the MTL, the lateral entorhinal cortex (LEC) and its downstream target the dentate/CA3 subfields of the hippocampus, as a distinctive feature that associates with impaired memory in aged individuals. A wealth of experimental and theoretical studies indicates that the deleterious consequences of hyperactivity are multiple. Hyperactivity not only compromises normal neural processing and the recruitment of plasticity mechanisms required for encoding new memories, but it can also accelerate activity dependent pathogenic processes, like Aβ production/deposition and spread of tau-hyperphosphorylation/toxicity along neural connections. In multiple brain areas, network activity is dynamically controlled primarily by GABAergic circuits subserved by parvalbumin-positive inhibitory interneurons (PV-INs). Importantly, mounting evidence indicates that dysfunction of these inhibitory circuits is a contributing factor in age-related hyperexcitability, particularly in the earliest phases of AD. In adults, the inhibitory output of the PV-INs is relatively stable, but the excitatory input onto PV-INs is comparatively dynamic and plastic. In this context, a particularly interesting research target for hyperxcitability during aging is Neuronal Pentraxin-2 (NPTX2), an extracellular protein released by excitatory neurons in an activity-dependent manner that is crucial for stabilizing AMPA receptors at synapses on PV-INs. Importantly, the genetic ablation of NPTX2 reduces these excitatory inputs by half in mouse cortex, and in elderly humans low levels of NPTX2 in the cerebral spinal fluid (CSF) correlates with reduced cognitive performance across the spectrum of aging/AD. In this proposal we will examine the novel hypothesis that a reduction in NPTX2- mediated stabilization of the excitatory connectivity onto PV-INs contributes to cognitive impairment during aging. We will directly evaluate the functional status of multiple excitatory inputs onto PV-INs within the MTL in a well-characterized rat model for individual cognitive differences in aging. We will also test whether manipulating NPTX2 affects these inputs as expected from the hypothesis. Testing the causal effect of NPTX2 in age-dependent cognitive impairment in a comprehensive manner in multiple pathways, might help identifying potential therapeutic targets to can alleviate age related cognitive decline.

衰老经常损害与内侧颞叶相关的认知功能