Khodosevich Group

Our group studies mechanisms that are responsible for neuronal specification, positioning and circuit formation during prenatal and postnatal brain development, and how these mechanisms contribute to neurodevelopmental disorders (schizophrenia, epilepsy, autism).

Developing mouse brain, green cells are migrating immature neurons.

Aim

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?
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

Psychiatric/neurodevelopmental risk factors

Response to genetic and environmental risk factors determines the vulnerability of neurons to psychiatric/neurodevelopmental disorders.
Read: Mol Psychiatry, Biol Psychiatry, Mol Psychiatry, Prog Neurobiol, EMBO J
The vulnerability of neurons strongly depends on the developmental period; thus, there are critical windows during which different types of neurons are particularly vulnerable or, conversely, resilient, and these periods vary across neuronal types.
Read: Mol Psychiatry, Biol Psychiatry, Mol Psychiatry
Our studies of specific risk factors:
- Maternal inflammation.
  Read: Mol Psychiatry
- Preterm birth.
  Read: Science Advances, Cell Reports
- 15q13.3 microdeletion.
  Read: Neuron, Biol Psychiatry
- Copy number variants (CNVs) in general.
  Read: Biol Psychiatry, Biol Psychiatry

Schizophrenia – neurodevelopmental etiology

Although the phenotypic manifestations of schizophrenia emerge only during adolescence or early adulthood, the initial mechanisms that may trigger schizophrenia-associated brain dysfunction are already detectable during embryonic development.
Read: Neuron, Biol Psychiatry, Biol Psychiatry
The upper layers of the prefrontal cortex are most affected in schizophrenia and may represent a core substrate underlying the disorder’s symptomatology
Read: Science Advances
Long-range Somatostatin neurons as potential pacemakers of schizophrenia-related brain dysfunction.
Read: Neuron
Novel framework to idenfity disease mechanisms and drug targets in schizophrenia and psychiatric disorders in general.
Read: Nat Rev Drug Discov, Mol Psychiatry

Psychiatric and neurological brain disorders at single-cell resolution

Schizophrenia: Upper cortical layer–driven network impairment in schizophrenia.
Read: Science Advances
Developmental epilepsy - Temporal lobe epilepsy: Epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis.
Read: Nat Commun
Developmental epilepsy – Tuberous sclerosis complex: Molecular structure preservation and massive reorganization of metabolism.
Read: bioRxiv

Main projects

Normal brain development

Neuronal specification in normal brain.
Maturation of cortical GABAergic neurons.

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

Major Experimental papers

Asenjo-Martinez A^#, Dragicevic K^#, Hou WH^#, Ozsvar A, Hansen N, Pfisterer U, Rydbirk R, Demharter S, Møller B, Gasthaus J, Korshunova I, Perrier JF, Capogna M, Vasistha NA^#, Khodosevich K^# (2025) Dysfunction of cortical GABAergic projection neurons as a major hallmark in a model of neuropsychiatric syndrome. Neuron, 113(19):3204-3223.e11

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, 25: 2313–2329

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

Major Computational papers

Malwade S, Sellgren C, Vasistha NA^#, Khodosevich K^# (2025) Rare copy number variants reveal critical cell types and periods of brain development in neurodevelopmental disorders. Biol Psychiatry: GOS, 5(4):100495

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, 16: 695–698

Major Reviews & Perspectives

Malwade S, Ingason A, Khodosevich K. (2025) The Use of Single-Cell and Spatial Omics to Study Copy Number Variants. Biol Psychiatry. Jun 20:S0006-3223(25)01269-7.

Khodosevich K, Dragicevic K, Howes O. (2024) Drug targeting in psychiatric disorders – how to overcome the loss in translation? Nat Rev Drug Discovery, 23: 218–231

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

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