CA1 pyramidal neuron profiling in female Down syndrome mice
What is it about?
Background: Individuals with Down syndrome (DS) have intellectual disability and develop Alzheimer’s disease (AD) pathology during midlife, particularly in the hippocampus which underlies learning, memory, and contributes to executive function . However, molecular and cellular mechanisms underlying the selective vulnerability of hippocampal CA1 neurons remains a major knowledge gap during the onset in DS. 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 specific sectors of the hippocampus, including the CA1 region. Objective: 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. Methods: Laser capture microdissection was performed on trisomic CA1 PNs in an established mouse model of DS/AD compared and disomic controls, isolating the entire CA1 pyramidal neuron layer, and subregional isolations of deep and superficial PNs from the CA1 region termed the CA1a sector. Results: RNA sequencing and bioinformatic inquiry revealed dysregulation of CA1 PNs based on spatial location and innervation patterns. Specifically, 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. Conclusions: 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.
Why is it important?
We interrogated 3 PN populations (CA1 deep, CA1 superficial, and CA1 total) in the CA1a sector of the hippocampus and found both overlapping and unique DEGs and pathways in trisomic mice compared to disomic controls. We postulate gene expression changes underlie behavioral and circuitry deficits in this mouse model of DS/AD. Approximately half (49.2%) of the convergently dysregulated DEGs were triplicated orthologs of the HSA21 chromosome. This finding affirms copy number overexpression of these ‘DS region’ genes throughout the CA1a sector and validates use of the Ts2 mouse to model CA1 pyramidal neuron defects in DS. In sum, CA1 deep PNs in the revealed significant deficits in key DEGs and pathways in older female Ts2 compared to 2N mice, which result in more functional alterations than CA1 all PNs or CA1 superficial PNs. The present study identified putative CA1 deep PNs targets for the amelioration of circuitry dependent deficits related to the aging hippocampus and targets for drug discovery in individuals with DS with translation to AD.