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

衰老经常损害与内侧颞叶相关的认知功能 (MTL)，特别是新记忆的形成，也是 阿尔茨海默病(AD)。最近对啮齿动物模型和人类的研究发现了多动症 在MTL的特定回路/亚区，外侧内嗅皮层(LEC)及其下游 以海马齿状/CA3亚区为靶点，将其作为与 老年人记忆力受损。丰富的实验和理论研究 这表明多动症的有害后果是多方面的。多动症不仅仅是 损害正常的神经处理和所需的可塑性机制的招募 用于编码新的记忆，但它也可以加速依赖活动的致病过程， 类β的产生/沉积和tau过度磷酸化/毒性沿神经的扩散 关系。 在多个大脑区域，网络活动主要由GABA能动态控制 由小白蛋白阳性抑制性中间神经元(PV-INS)支持的回路。重要的是 越来越多的证据表明，这些抑制回路的功能障碍是导致 年龄相关的过度兴奋性，特别是在AD的早期阶段。在成年人中，抑制作用 PV-INS的输出相对稳定，但对PV-INS的兴奋性输入相对稳定 动感的和塑料的。在这种情况下，一个特别有趣的研究目标是过度兴奋 在衰老过程中的是神经元五角蛋白-2(NPTX2)，这是一种由兴奋性释放的细胞外蛋白 神经元的活动依赖方式，这是稳定AMPA受体的关键 PV-in上的突触。重要的是，NPTX2的基因消融减少了这些兴奋性输入 小鼠皮质中NPTX2水平降低一半，老年人脑脊液中NPTX2水平较低 (脑脊液)与衰老/阿尔茨海默病的认知能力下降有关。 在这个提议中，我们将检验新的假设，即NPTX2的减少- 介导的兴奋性连接对PV-INS的稳定作用有助于认知 衰老过程中的损伤。我们将直接评估多个兴奋性神经的功能状态 在个体认知良好的大鼠模型中，对MTL内PV-IN的输入 年龄上的差异。我们还将测试操作NPTX2是否会影响这些输入 从假设中可以预料到。NPTX2在年龄依赖性认知中的因果效应检验 多个途径的综合损伤可能有助于识别潜在的 治疗的目标是可以缓解与年龄相关的认知衰退。

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.