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

Article type: Research Article

Authors: Alldred, Melissa J.^{a; b} | Pidikiti, Harshitha^a | Ibrahim, Kryillos W.^a | Lee, Sang Han^{a; b} | Heguy, Adriana^c | Hoffman, Gabriel E.^f | Mufson, Elliott J.^g | Stutzmann, Grace E.^h | Ginsberg, Stephen D.^{a; b; d; e; *}

Affiliations: [a] Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA | [b] Departments of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA | [c] Genome Technology Center, New York University Grossman School of Medicine, New York, NY, USA | [d] Neuroscience & Physiology, New York University Grossman School of Medicine, New York, NY, USA | [e] NYU Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, USA | [f] Departments of Genetics and Genomic Sciences and Psychiatry and the Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA | [g] Department of Translational Neuroscience and Neurology, Barrow Neurological Institute, Phoenix, AZ, USA | [h] Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University/The Chicago Medical School, North Chicago, IL, USA

Correspondence: [*] Correspondence to: Stephen D. Ginsberg, PhD, Center for Dementia Research, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. Tel.: +1 845 398 2170; Fax: +1 845 398 2197; E-mail: [email protected].

Abstract: Background: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. 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 to disomic controls, isolating the entire CA1 pyramidal neuron layer and sublayer microisolations of deep and superficial PNs from the distal CA1 (CA1a) region. Results: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. 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.

Keywords: Alzheimer’s disease, bioinformatics, CA1, circuitry, Down syndrome, hippocampus, laser capture microdissection, RNA-seq, selective vulnerability, trisomy

DOI: 10.3233/JAD-240622

Journal: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S341-S362, 2024