Biology subjects

Pfisterer, U.

Publications and source records attributed to Pfisterer, U..

3 recordsLinked to original sources

bioRxiv2020

Selective vulnerability of supragranular layer neurons in schizophrenia

Schizophrenia is one of the most wide-spread mental brain disorders with complex and largely unknown etiology. To characterize the impact of schizophrenia at a cellular level, we performed single nucleus RNA sequencing of >190,000 neurons from the dorsolateral prefrontal cortex of patients with schizophrenia and matched controls (7 vs 11, respectively). In addition, to correlate data with cortical anatomy, >100,000 neurons were analyzed topographically by immunohistochemistry in an extended cohort of cases with schizophrenia and controls (10 vs 10). Compositional analysis of RNA sequencing data revealed reduction in relative abundance across all families of GABAergic neurons and a concomitant increase in principal neurons, which was most pronounced for supragranular subtypes (layers 2-3). Moreover, supragranular subtypes of GABAergic interneurons showed most dramatic transcriptomic changes. These results were substantiated by histological analysis, which revealed a reduction in the density of calretinin, calbindin and parvalbumin GABAergic interneurons particularly in layer 2. Common effect of schizophrenia on supragranular neuronal networks was underlined by downregulation of protein processing genes and upregulation of neuronal development/plasticity genes across supragranular subtypes of principal neurons and GABAergic interneurons. In situ hybridization and spatial transcriptomics further confirmed supragranular layer neuron vulnerability, revealing complexity of schizophrenia-affected cortical circuits. These point towards general network impairment within supragranular layers being a core substrate associated with schizophrenia symptomatology.

neuroscience↗

bioRxiv2019

Sandwich cortical lamination and single-cell analysis decodes the developing spatial processing system.

Classic studies investigating how and when the entorhinal cortex (component of the memory processing system of the brain) develops have been based on traditional thymidine autoradiography and histological techniques. In this study, we take advantage of modern technologies to trace at a high resolution, the cellular complexity of the developing porcine medial entorhinal cortex by using single-cell profiling. The postnatal medial entorhinal cortex comprises 4 interneuron, 3 pyramidal neuron and 2 stellate cell populations which emerge from intermediate progenitor and immature neuron populations. We discover four MGE-derived interneurons and one CGE-derived interneuron population as well as several IN progenitors. We also identify two oligodendrocyte progenitor populations and three populations of oligodendrocytes. We perform a proof-of-concept experiment demonstrating that porcine scRNA-seq data can be used to develop novel protocols for producing human entorhinal cells in-vitro. We identified six transcription factors (RUNX1A1, SOX5, FOXP1, MEF2C, TCF4, EYA2) important in neurodevelopment and differentiation from one RELN+ stellate cell population. Using a lentiviral vector approach, we reprogrammed human induced pluripotent stem cells into stellate cell-like cells which expressed RELN, SATB2, LEF1 and BCL11B. Our findings contribute to the understanding of the formation of the brains cognitive memory and spatial processing system and provides proof-of-concept for the production of entorhinal cells from human pluripotent stem cells in-vitro.

developmental biology↗

bioRxiv2018

Maternal inflammation significantly impacts cortical interneuron development in a subtype-specific manner

Severe infections during pregnancy are one of the major risk factors for cognitive brain impairment in offspring. It has been suggested that maternal inflammation leads to dysfunction of cortical GABAergic interneurons that in turn underlies cognitive impairment of the affected offspring. However, the evidence comes largely from studies of adult or mature brain and how impairment of inhibitory circuits arises upon maternal inflammation is unknown. Here we show that maternal inflammation affects multiple steps of cortical GABAergic interneuron development, i.e. proliferation of precursor cells, migration and positioning of neuroblasts as well as neuronal maturation. Importantly, the development of distinct subtypes of cortical GABAergic interneurons was discretely impaired as a result of maternal inflammation. This translated into a reduction in cell numbers, redistribution across cortical regions and layers, changes in morphology and cellular properties. Furthermore, selective vulnerability of GABAergic interneuron subtypes was associated with the stage of brain development. Thus, we propose that maternally-derived insults have developmental stage-dependent effects which contribute to the complex etiology of cognitive impairment in the affected offspring.

neuroscience↗