Induced neural progenitor cells and iPS-neurons from major depressive disorder patients show altered bioenergetics and electrophysiological properties

Triebelhorn, Julian; Cardon, Iseline; Kuffner, Kerstin; Bader, Stefanie; Jahner, Tatjana; Meindl, Katrin; Rothhammer-Hampl, Tanja; Riemenschneider, Markus J.; Drexler, Konstantin; Berneburg, Mark; Manook, André; Brochhausen, Christoph; Baghai, Thomas C.; Hilbert, Sven; Rupprecht, Rainer; Milenkovic, Vladimir M.; Wetzel, Christian H.

doi:10.1038/s41380-022-01660-1

Cited by 18 publications

(62 citation statements)

References 59 publications

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“…We then reprogrammed the fibroblasts to induced pluripotent stem cells (iPSCs) which we subsequently differentiated to neural progenitor cells (NPCs) and neurons. Like in peripheral cells, we observed signs of altered mitochondrial function in the neural lineage including lower respiration rates 30 . In neurons, electrophysiological measurements showed significantly lower membrane capacitance, a more depolarized membrane potential, and increased spontaneous electrical activity 30 .…”

Section: Introductionmentioning

confidence: 58%

“…Like in peripheral cells, we observed signs of altered mitochondrial function in the neural lineage including lower respiration rates 30 . In neurons, electrophysiological measurements showed significantly lower membrane capacitance, a more depolarized membrane potential, and increased spontaneous electrical activity 30 .…”

Section: Introductionmentioning

confidence: 58%

“…In the present study we compare cellular models from two specific patients with data previously obtained in a cohort of MDD patients in order to extend our knowledge on the biological mechanisms underpinning the development of MDD 29,30 .…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial and cellular function in fibroblasts and reprogrammed neural cells: insights into major depression as a mitochondria-associated disease

Wetzel,

Cardon,

Grobecker

et al. 2023

Preprint

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The neurobiological underpinnings of major depressive disorder (MDD) remain still elusive. Meanwhile, mitochondria and energy metabolism turn into focus as relevant pathomechanisms of MDD. To gain further insight on the role of mitochondria function in MDD, in the present work, we examined the functional cellular and mitochondrial properties in cells derived from two specific patients, diagnosed as suffering from a mild form of mitochondriopathy with unknown cause, and an antidepressant non-responding MDD patient and compared these patients to a cohort of MDD and control subjects. Using skin biopsies of the two patients as well as non-depressed healthy controls, we obtained dermal fibroblasts and generated iPSCs, neural progenitors, neurons, and astrocytes. Notably, we observed that cellular and mitochondrial functions and neuronal electrophysiology in the mitochondriopathy patient resembled findings in the MDD cohort. This included decreased respiration, mitochondrial membrane potential (MMP) and depolarized resting membrane potential, associated with smaller sodium currents. In contrast, cells derived from the non-responder MDD patient were affected in an opposite manner in many of the measured parameters, including increased respiratory rates, mitochondrial calcium, and lower resting membrane potential. However, in all patient cells we consistently observed a smaller cell size compared to healthy controls. Our findings revealed marked similarities between the mitochondriopathy patient and the MDD cohort, supporting the hypothesis that mitochondria play a significant role in the pathophysiology of depression. The overall opposite functional phenotype of the non-responder patient pointed towards distinct or counterregulatory mechanisms involved in the etiology and/or treatment resistance of depression in this patient and emphasized the importance of investigating depression-related phenotypes from different disease entities to gain a more comprehensive understanding of the pathology of MDD.

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Section: Introductionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 58%

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Mitochondrial and cellular function in fibroblasts and reprogrammed neural cells: insights into major depression as a mitochondria-associated disease

Wetzel,

Cardon,

Grobecker

et al. 2023

Preprint

Self Cite

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“…Cerebrospinal fluid (CSF) level of MMP2 was significantly higher in patients with major depression [62] while peripheral levels of MMP2 were significantly lower in patients with mood disorders [63]. A recent study showed that iPSC-derived NPCs and neurons from MDD patients had decreased basal respiration and increased spontaneous electrical activity, respectively [64]. iPSC-derived GABA interneurons from suicide attempters with major depression showed increased neurite branches, electrophysiological hyperexcitability, and decreased calcium signaling [65].…”

Section: Discussionmentioning

confidence: 99%

Altered transcriptomes, cell type proportions, and dendritic spine morphology in hippocampus of suicide deaths

Das

Schulmann

Callor

et al. 2023

Preprint

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Suicide is a condition resulting from complex environmental and genetic risks that affect millions of people globally. Both structural and functional studies identified the hippocampus as one of the vulnerable brain regions contributing to suicide risk. Here, we have identified the hippocampal transcriptomes, gene ontology, cell type proportions, dendritic spine morphology, and transcriptomic signature in iPSC-derived neuronal precursor cells (NPCs) and neurons in postmortem brain tissue from suicide deaths. The hippocampal tissue transcriptomic data revealed that NPAS4 gene expression was downregulated while ALDH1A2, NAAA, and MLXIPL gene expressions were upregulated in tissue from suicide deaths. The gene ontology identified 29 significant pathways including NPAS4-associated gene ontology terms 'excitatory post-synaptic potential', 'regulation of postsynaptic membrane potential' and 'long-term memory' indicating alteration of glutamatergic synapses in the hippocampus of suicide deaths. The cell type deconvolution identified decreased excitatory neuron proportion and an increased inhibitory neuron proportion providing evidence of excitation/inhibition imbalance in the hippocampus of suicide deaths. In addition, suicide deaths had increased dendric spine density, due to an increase of thin (relatively unstable) dendritic spines, compared to controls. The transcriptomes of iPSC-derived hippocampal-like NPCs and neurons revealed 31 and 33 differentially expressed genes in NPC and neurons, respectively, of suicide deaths. The suicide-associated differentially expressed genes in NPCs were RELN, CRH, EMX2, OXTR, PARM1 and IFITM2 which overlapped with previously published results. The previously-known suicide-associated differentially expressed genes in differentiated neurons were COL1A1, THBS1, IFITM2, AQP1, and NLRP2. Together, these findings would help better understand the hippocampal neurobiology of suicide for identifying therapeutic targets to prevent suicide.

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“…On-going efforts are identifying other mechanisms by which variants impact gene regulation, such as through detection of chromatin QTLs, cell fraction QTLs, and chromatin conformational changes 22 . Psychiatric disorders have also been associated with changes in diverse cellular phenotypes such as cell adherence [23][24][25] , cellular energetics 26,27 , and neuron electrophysiological response patterns 26,28 . In a limited number of cases, causal links between psychiatric genetic variants and changes in cellular phenotypic variation have been established.…”

Section: Introductionmentioning

confidence: 99%

Cell adhesion molecules play subclass-specific roles in electrophysiological response and Schizophrenia risk

Johansen

et al. 2022

Preprint

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Multimodal assays such as Patch-seq that simultaneously profile molecular and cellular phenotypes of cells enable the identification of molecular underpinnings of electrophysiological response patterns in neurons. Here we analyzed Patch-seq measurements of thousands of mouse interneurons to identify subclass-specific genes associated with different electrophysiological features. We found extensive subclass specificity: even for the same ephys feature, largely unique sets of genes are associated with that feature in different subclasses. Well established ephys genes such as Reln demonstrated subclass specificity that was previously not reported. Surprisingly, we found that ion channels explained significantly less variation in ephys response across interneurons compared to other genes; in particular, gene sets enriched in cell adhesion genes were amongst the most associated. We found our gene sets associated with action potential dV/dt measurements explained significant heritability of Schizophrenia risk, suggesting a novel role of single neuron electrophysiology in Schizophrenia risk. Finally, we observed significant ephys function switching of cell adhesion molecules across subclasses; the same adhesion molecule was observed to associate with different functional ephys measurements in distinct subclasses and co-express with different genes, suggesting re-purposing of adhesion molecules in different subclasses. Overall, our results yield novel insight into the specificity of roles that individual genes and adhesion molecules play in both single neuron ephys response and Schizophrenia risk.

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Induced neural progenitor cells and iPS-neurons from major depressive disorder patients show altered bioenergetics and electrophysiological properties

Cited by 18 publications

References 59 publications

Mitochondrial and cellular function in fibroblasts and reprogrammed neural cells: insights into major depression as a mitochondria-associated disease

Mitochondrial and cellular function in fibroblasts and reprogrammed neural cells: insights into major depression as a mitochondria-associated disease

Altered transcriptomes, cell type proportions, and dendritic spine morphology in hippocampus of suicide deaths

Cell adhesion molecules play subclass-specific roles in electrophysiological response and Schizophrenia risk

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