Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Campus Juriquilla, Querétaro, México.
Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Campus Juriquilla, Querétaro, México.
Neuroscience. 2022 Aug 21;498:260-279. doi: 10.1016/j.neuroscience.2022.07.006. Epub 2022 Jul 15.
Prefrontal cortex (PFC)-related functions, such as working memory (WM) and cognitive flexibility (CF), are among the first to be altered at early stages of Alzheimer's disease (AD). Likewise, transgenic AD models carrying different AD-related mutations, mostly linked to the overproduction of amyloid beta (Aβ) and other peptides, show premature behavioral and functional symptoms associated with PFC alterations. However, little is known about the effects of intracerebral or intra-PFC Aβ infusion on WM and CF, as well as on pyramidal cell excitability and plasticity. Thus, here we evaluated the effects of a single Aβ injection, directly into the PFC, or its intracerebroventricular (icv) application, on PFC-dependent behaviors and on the intrinsic and synaptic properties of layer V pyramidal neurons in PFC slices. We found that a single icv Aβ infusion reduced learning and performance of a delayed non-matching-to-sample WM task and prevented reversal learning in a matching-to-sample version of the task, several weeks after its infusion. The inhibition of WM performance was reproduced more potently by a single PFC Aβ infusion and was associated with Aβ accumulation. This behavioral disruption was related to increased layer V pyramidal cell firing, larger sag membrane potential, increased fast after-hyperpolarization and a failure to sustain synaptic long-term potentiation, even leading to long-term depression, at both the hippocampal-PFC pathway and intracortical synapses. These findings show that Aβ can affect PFC excitability and synaptic plasticity balance, damaging PFC-dependent functions, which could constitute the foundations of the early alterations in executive functions in AD patients.
前额叶皮层（PFC）相关功能，如工作记忆（WM）和认知灵活性（CF），是在阿尔茨海默病（AD）的早期阶段首先改变的功能之一。同样，携带不同 AD 相关突变的转基因 AD 模型，主要与淀粉样β（Aβ）和其他肽的过度产生有关，表现出与 PFC 改变相关的过早行为和功能症状。然而，关于脑内或 PFC 内 Aβ输注对 WM 和 CF 以及锥体神经元兴奋性和可塑性的影响知之甚少。因此，在这里我们评估了单次 Aβ注射，直接注入 PFC，或其脑室（icv）应用对 PFC 依赖性行为以及 PFC 切片中 V 层锥体神经元的内在和突触特性的影响。我们发现，单次 icv Aβ输注可降低延迟非匹配样本 WM 任务的学习和表现，并阻止在任务的匹配样本版本中进行反转学习，这发生在输注后数周。单次 PFC Aβ输注更强烈地再现了 WM 表现的抑制，并且与 Aβ的积累有关。这种行为障碍与 V 层锥体神经元放电增加、膜电位 sag 增大、快速后超极化增加以及在海马 - PFC 通路和皮质内突触处维持长时程增强的失败有关，甚至导致长时程抑郁。这些发现表明 Aβ 可以影响 PFC 兴奋性和突触可塑性平衡，破坏 PFC 依赖性功能，这可能构成 AD 患者执行功能早期改变的基础。
