Khodosevich Group

We aim to address the key questions for our understanding of brain function “how such complex organ as the brain is build up during development?” and “what goes wrong in neurodevelopmental disorders?”.

Vision & research questions

We study mechanisms that are responsible for neuronal specification, positioning and circuit formation during brain development, and how these mechanisms are impaired in neurodevelopmental disorders, such as schizophrenia, epilepsy, autism and others. In particular, we investigate how genetics and environment shape brain development and determine the vulnerability of neurons to developmental disorders.

Main findings

Response to genetic and environmental stimuli determines the vulnerability of neurons to neurodevelopmental disorders.
The vulnerability of neurons is highly dependent on developmental period; thus, there are critical periods of development, when different types of neurons are particularly vulnerable, or particularly resilient, and these periods differ for different neuronal types

Read papers: Maternal inflammation has a profound effect on cortical interneuron development in a stage and subtype-specific manner & Identification of Vulnerable Interneuron Subtypes in 15q13.3 Microdeletion Syndrome Using Single-Cell Transcriptomics

Neuronal types, circuits and gene expression at single-cell resolution that contribute to epilepsy and schizophrenia in human brain.

Read papers: Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis & Selective vulnerability of supragranular layer neurons in schizophrenia

Identification of a pivotal metabolic gene to pair energy production and energy demand in fast-spiking interneurons (the key neurons in neurodevelopmental disorders)
Specific metabolism of fast-spiking interneurons programs their neuronal maturation, and when impaired leads to neuropsychiatric phenotype

Read paper: Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports their function

Main projects

Normal brain development

Neuronal specification in normal brain.
Maturation of cortical interneurons.

Neurodevelopmental disorders

Epilepsy:
- Mechanisms of epileptogenesis in human tissue and animal models.
- Functional characterization of human neurons in epileptic tissue
Schizophrenia:
- Effects of environmental factors, such as maternal viral infections, inflammation, and pre-term birth on fetal brain development and postnatal brain maturation.
- Effects of schizophrenia-associated genetic mutations on fetal brain development and postnatal brain maturation.
- Formation of neuronal circuits underlying schizophrenia.
- Metabolic impairment in schizophrenia.

Technology

Single Cell Omics and Spatial Analysis

We are working to understand brain development and neurodevelopmental disorders at a molecular scale, and how various molecular perturbations alter the brain function. Our research extends from studying disease model rodent brains to human patient brain tissues. We apply single-cell and single-nucleus omics as well as spatial omics methods to profile molecular and spatial alterations in the tissue. Our approach provides a comprehensive insight into the alterations underlying impaired brain function in neurodevelopmental disorders.

Lab

High-throughput profiling: We use the 10X Genomics Chromium platform. This droplet-based method enables profiling of several thousand of cells or nuclei in a parallel manner and thus permits the exploration of the cellular composition of a given tissue.
High-resolution profiling: We use Smart-seq2 for high-resolution profiling of single-cells or nuclei. This method provides greater sequencing depth and thus potentially allows detecting subtle molecular alterations in the normal and disordered brain.
Spatial profiling: We implement spatial analysis based on 10X Genomics Chromium platform allowing us to identify changes in cell composition and spatial location of molecular changes in disordered brains.

Bioinformatics

Following single-cell RNA sequencing, downstream analysis involves

Identification of differentially expressed genes and pathways

Clustering of the cells according to their gene expression

Visualisation and interactive exploration of the data

Characterisation of the disease-related changes

Integration of several modalities of single cell data (e.g. transcriptome and epigenome), integration with genetics, with spatial data etc.

Tools we commonly use for these tasks include the packages Cacoa, Conos, Pagoda 2, velocyto, scanpy and paga, as well as pipelines as dropest, CellRanger, stereoscope and CellPhoneDB.

Publications

Selected publications

Experimental papers

Batiuk M^#, Tyler T^#, Dragicevic K, Mei S, Rydbirk R, Petukhov V, Deviatiiarov R, Sedmak D, Frank E, Feher V, Habek N, Hu Q, Igolkina A, Roszik L, Pfisterer U, Garcia-Gonzalez D, Petanjek Z, Adorjan I, Kharchenko P, Khodosevich K (2022) Upper cortical layer–driven network impairment in schizophrenia. Sci Adv 8, eabn8367

Malwade S, Gasthaus J, Bellardita C, Andelic M, Moric B, Korshunova I, Kiehn O, Vasistha NA, Khodosevich K. (2022) Identification of vulnerable interneuron subtypes in 15q13.3 microdeletion syndrome using single-cell transcriptomics. Biol Psychiatry, 91(8): 727-739

Pfisterer^#, Demharter S.^#, Petukhov V.^#, MeichsnerJ.^#, ThompsonJ., BatiukM., Asenjo MartinezA., VasisthaN., ThakurA., MikkelsenJ., AdorjanI., PinborgL., PersT., von EngelhardtJ., KharchenkoP., Khodosevich K. (2020) Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis. Nat Commun, 11(1):1-19

Vasistha N.^#, Pardo-Navarro M.^#, Gasthaus J., Weijers D., Müller M., García-González D., Malwade S., Korshunova I., Pfisterer U., von Engelhardt J., Hougaard K., Khodosevich K. (2019) Maternal inflammation has a profound effect on cortical interneuron development in a stage and subtype-specific manner. Mol Psychiatry, 10.1038/s41380-019-0539-5

Sanz Morello B., Pfisterer U., Hansen N., Demharter S., Thakur A., Fujii K., Levitskiy S., Montalant A., Korshunova I., Mammen P., Kamenski P., Noguchi S., Aldana Garcia B., Hougaard K., Perrier J., Khodosevich K. (2020) Unique isoform in oxidative phosphorylation machinery supports the function of fast-spiking neurons. EMBO J, 39(18):e105759

Computational papers

Petukhov V#, Igolkina A#, Rydbirk R, Mei S, Christoffersen L, Khodosevich K#, Kharchenko P# (2022). Case-control analysis of single-cell RNA-seq studies. bioRxiv 2022.03.15.484475.

Petukhov V, Xu R, Soldatov RA, Cadinu P, Khodosevich K, Moffitt J, Kharchenko P. (2021) Cell segmentation in imaging-based spatial transcriptomics. Nat Biotech, 40(3): 345-354

Barkas N.#, Petukhov V.#, Nikolaeva D., Lozinsky Y., Demharter S., Khodosevich K., Kharchenko PV. (2019). Joint analysis of heterogeneous single-cell RNA-seq dataset collections. Nat Methods, 2019 Jul 15. doi: 10.1038/s41592-019-0466-z.

Reviews & Perspectives

Khodosevich K, Dragicevic K, Howes O. (2023) Drug targeting in psychiatric disorders – how to overcome the loss in translation? Nat Rev Drug Discovery, s41573-023-00847-7

Khodosevich K, Sellgren CM. (2023) Neurodevelopmental disorders—high-resolution rethinking of disease modeling. Mol Psychiatry 28(1):34-43

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