Hippocampal CA1 Pyramidal Neurons Display Sublayer and Circuitry Dependent Degenerative Expression Profiles in Aged Female Down Syndrome Mice

People with Down syndrome (DS) have intellectual disability (ID) and develop hallmark Alzheimer’s disease (AD) pathology during midlife. There are several circuits underlying memory and executive function in the DS and AD brain that are particularly vulnerable and degenerate early in disease, most notably the septohippocampal circuit and the trisynaptic loop in the hippocampus. A fundamental lack of knowledge exists as to the etiology and mechanisms of disease progression within these critical circuits vulnerable to degeneration in DS, AD, and relevant models. This is compounded by new evidence that suggests spatial localization of neurons has profound effects on activity and innervation within the hippocampal CA1 region. We postulated gene expression changes in a DS mouse model, at a time that these circuits of input to the CA1 are degraded, would have a significant effect on gene expression in CA1 pyramidal neurons. Further, this dysfunction may be specific to spatial localization and innervation. Laser capture microscopy on pyramidal neurons from CA1 was performed, isolating the entire CA1 pyramidal neuron layer, which was compared to select populations of deep and superficial pyramidal neurons from CA1a (distal CA1, adjacent to the subiculum). RNA-seq and bioinformatic analysis was performed where profound differences in dysregulation in the DS mouse model based on their spatial location and postulated circuitry were examined.