Biology subjects

Schmidt, E. F.

Publications and source records attributed to Schmidt, E. F..

5 recordsLinked to original sources

bioRxiv2026

Divergent mitochondrial and metabolic adaptations shape selective vulnerability in ALS

Neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) exhibit striking cell-type selectivity, yet the basis for this vulnerability remains elusive. Here, we uncover that even closely related neurons can harbor distinct mitochondrial properties that shape their response to disease. Using TOM-Tag, a circuit-based AAV-based strategy for cell type-specific mitochondrial immunopurification from projection neurons, we performed integrative proteomic, metabolomic, transcriptomic, and functional analyses of mitochondria from ALS-vulnerable corticospinal projection neurons (CSPNs) and resilient corticothalamic projection neurons (CTPNs) in vivo. We discovered that CSPNs and CTPNs exhibit divergent mitochondrial profiles at baseline, despite sharing cortical layer and developmental origin. CTPNs were primed for antioxidant buffering and fatty acid metabolism, whereas CSPNs were enriched for oxidative phosphorylation components. In ALS, CTPNs employed mitochondrial flexibility and redox defense, whereas CSPNs exhibited respiratory failure and metabolic stress. These findings reveal that intrinsic mitochondrial programs vary even between similar neurons, and that this hidden layer of diversity may critically shape susceptibility to neurodegeneration. By enabling high-resolution access to mitochondria in defined neuronal circuits, TOM-Tag offers a powerful new lens for dissecting disease mechanisms and identifying cell-specific therapeutic targets.

neuroscience↗

bioRxiv2024

Spontaneously regenerative corticospinal neurons in mice

The spinal cord receives inputs from the cortex via corticospinal neurons (CSNs). While predominantly a contralateral projection, a less-investigated minority of its axons terminate in the ipsilateral spinal cord. We analyzed the spatial and molecular properties of these ipsilateral axons and their post-synaptic targets in mice and found they project primarily to the ventral horn, including directly to motor neurons. Barcode-based reconstruction of the ipsilateral axons revealed a class of primarily bilaterally-projecting CSNs with a distinct cortical distribution. The molecular properties of these ipsilaterally-projecting CSNs (IP-CSNs) are strikingly similar to the previously described molecular signature of embryonic-like regenerating CSNs. Finally, we show that IP-CSNs are spontaneously regenerative after spinal cord injury. The discovery of a class of spontaneously regenerative CSNs may prove valuable to the study of spinal cord injury. Additionally, this work suggests that the retention of juvenile-like characteristics may be a widespread phenomenon in adult nervous systems.

neuroscience↗

bioRxiv2021

Unique molecular features and cellular responses differentiate two populations of motor cortical layer 5b neurons in a preclinical model of ALS.

Many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), lead to the selective degeneration of discrete cell types in the CNS despite the ubiquitous expression of many genes linked to disease. Therapeutic advancement depends on understanding unique cellular adaptations that underlie pathology of vulnerable cells in the context of disease-causing mutations. Here, we employ bacTRAP molecular profiling to elucidate cell type specific molecular responses of cortical upper motor neurons in a preclinical ALS model. Using two bacTRAP mouse lines that label distinct vulnerable or resilient projection neuron populations in motor cortex, we show that the regulation of oxidative phosphorylation (Oxphos) pathways is a common response in both cell types. However, differences in the baseline expression of genes involved in Oxphos and the handling of reactive oxygen species likely lead to the selective degeneration of the vulnerable cells. These results provide a framework to identify cell type-specific processes in neurodegenerative disease.

neuroscience↗

bioRxiv2019

Serotonin receptor 4 in mature excitatory hippocampal neurons modulates mood and anxiety

Serotonin receptor 4 (5-HT4R) plays an important role in regulating mood, anxiety, and cognition, and drugs that activate this receptor have fast-acting antidepressant (AD)-like effects in preclinical models. However, 5-HT4R is widely expressed throughout the central nervous system (CNS) and periphery, making it a poor therapeutic target and difficult to pinpoint the cell types and circuits underlying its effects. Therefore, we generated a Cre-dependent 5-HT4R knockout mouse line to dissect the function of 5-HT4R in specific brain regions and cell types. We show that the loss of functional 5-HT4R specifically in the mature excitatory neurons of hippocampus led to robust AD-like behavioral responses and an elevation in baseline anxiety. 5-HT4R was necessary to maintain the proper excitability of mature dentate gyrus (DG) granule cells and cell type specific molecular profiling revealed a dysregulation of genes necessary for normal neural function and plasticity in cells lacking 5-HT4R. These adaptations were accompanied by an increase in the number of immature neurons in ventral, but not dorsal, dentate gyrus, indicating a broad impact of 5-HT4R loss on the local cellular environment. This study is the first to use conditional genetic targeting to demonstrate a direct role for hippocampal 5-HT4R signaling in modulating mood and anxiety. Our findings also underscore the need for cell type-based approaches to elucidate the complex action of neuromodulatory systems on distinct neural circuits.

neuroscience↗

bioRxiv2018

Selective neuronal vulnerability in Alzheimer’s disease: a network-based analysis

A major obstacle to treating Alzheimers disease (AD) is our lack of understanding of the molecular mechanisms underlying selective neuronal vulnerability, which is a key characteristic of the disease. Here we present a framework to integrate high-quality neuron-type specific molecular profiles across the lifetime of the healthy mouse, which we generated using bacTRAP, with postmortem human functional genomics and quantitative genetics data. We demonstrate human-mouse conservation of cellular taxonomy at the molecular level for AD vulnerable and resistant neurons, identify specific genes and pathways associated with AD pathology, and pinpoint a specific functional gene module underlying selective vulnerability, enriched in processes associated with axonal remodeling, and affected by both amyloid accumulation and aging. Overall, our study provides a molecular framework for understanding the complex interplay between A{beta}, aging, and neurodegeneration within the most vulnerable neurons in AD.

neuroscience↗