■患有唐氏综合症(DS)的人在中年期间有智力障碍并发展为阿尔茨海默病(AD)病理,特别是在内侧颞叶记忆回路的海马部分。然而,海马CA1神经元选择性易损性的分子和细胞机制仍然是DS/AD发病期间的主要知识空白。这与显示空间的证据(例如,锥体神经元(PNs)的深层定位对CA1区域内的活动和神经支配具有深远的影响。
■我们调查了老年雌性DS/AD小鼠模型中CA1PN是否存在空间分布差异。我们认为功能障碍可能取决于离散CA1子场中的空间定位和神经支配模式。
■在已建立的DS/AD小鼠模型中,在三体CA1PNs上进行激光捕获显微解剖,从远端CA1(CA1a)区域分离整个CA1锥体神经元层和深层和浅表PN的亚层微隔离。
■RNA测序和生物信息学查询揭示了基于空间位置和神经支配模式的CA1PN的失调。在三体小鼠中,整个CA1区域显示出最多的差异表达基因(DEGs),反映了先天性DS的脆弱性,虽然三体CA1a深PN表现出更少但更多的生理相关DEG,生物信息学调查证明了这一点。
■CA1a深层神经元显示出许多与认知功能相关的DEG,而CA1a浅层神经元,DEG的数量大致相等,与失调的途径无关,表明易损CA1PN的空间位置在电路溶解中起着重要作用。
UNASSIGNED: Individuals with Down syndrome (DS) have intellectual disability and develop Alzheimer\'s disease (AD) pathology during midlife, particularly in the hippocampal component of the medial temporal lobe memory circuit. However, molecular and cellular mechanisms underlying selective vulnerability of hippocampal CA1 neurons remains a major knowledge gap during DS/AD onset. This is compounded by evidence showing spatial (e.g., deep versus superficial) localization of pyramidal neurons (PNs) has profound effects on activity and innervation within the CA1 region.
UNASSIGNED: We investigated whether there is a spatial profiling difference in CA1 PNs in an aged female DS/AD mouse model. We posit dysfunction may be dependent on spatial localization and innervation patterns within discrete CA1 subfields.
UNASSIGNED: Laser capture microdissection was performed on trisomic CA1 PNs in an established mouse model of DS/AD compared to disomic controls, isolating the entire CA1 pyramidal neuron layer and sublayer microisolations of deep and superficial PNs from the distal CA1 (CA1a) region.
UNASSIGNED: RNA sequencing and bioinformatic inquiry revealed dysregulation of CA1 PNs based on spatial location and innervation patterns. The entire CA1 region displayed the most differentially expressed genes (DEGs) in trisomic mice reflecting innate DS vulnerability, while trisomic CA1a deep PNs exhibited fewer but more physiologically relevant DEGs, as evidenced by bioinformatic inquiry.
UNASSIGNED: CA1a deep neurons displayed numerous DEGs linked to cognitive functions whereas CA1a superficial neurons, with approximately equal numbers of DEGs, were not linked to pathways of dysregulation, suggesting the spatial location of vulnerable CA1 PNs plays an important role in circuit dissolution.