Hippocampal subfield transcriptome analysis in schizophrenia psychosis

Perez, Jessica M.; Berto, Stefano; Gleason, Kelly; Ghose, Subroto; Tan, Chunfeng; Kim, Tae Kyung; Konopka, Genevieve; Tamminga, Carol A.

doi:10.1038/s41380-020-0696-6

Cited by 29 publications

(19 citation statements)

References 76 publications

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“…Interestingly, both excitatory and inhibitory neurons are enriched for SCZ risk variants. This result underscores hippocampal vulnerability in SCZ, which is in line with previous bulk RNA-seq analysis of SCZ-affected hippocampal tissue (Collado-Torres et al, 2019;Perez et al, 2020). Both ASD-and ADHD-linked risk loci are enriched in pyramidal neurons of CA1 (CA1.1 and CA1.2) and subiculum (Sub.)…”

Section: Transcriptomic Heterogeneity Of Dg Granule Cells In the Hippocampussupporting

confidence: 89%

Resolving cellular and molecular diversity along the hippocampal anterior-to-posterior axis in humans

Ayhan

Kulkarni

Berto

et al. 2021

Neuron

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Section: Transcriptomic Heterogeneity Of Dg Granule Cells In the Hippocampussupporting

confidence: 89%

Resolving cellular and molecular diversity along the hippocampal anterior-to-posterior axis in humans

Ayhan

Kulkarni

Berto

et al. 2021

Neuron

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“…almost certainly contribute to schizophrenia and to the clinical effect of clozapine. Furthermore, cortical location matters as well ( Collado-Torres et al, 2019 ; Perez et al, 2021 ). iPSC-derived glutamatergic neurons obviously cannot fully reflect the regional differences in local microenvironment extant in the intact brain.…”

Section: Discussionmentioning

confidence: 99%

Clozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive Schizophrenia Patients

Hříbková

Svoboda

Bartečků

et al. 2022

Front. Cell. Neurosci.

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The cellular pathology of schizophrenia and the potential of antipsychotics to target underlying neuronal dysfunctions are still largely unknown. We employed glutamatergic neurons derived from induced pluripotent stem cells (iPSC) obtained from schizophrenia patients with known histories of response to clozapine and healthy controls to decipher the mechanisms of action of clozapine, spanning from molecular (transcriptomic profiling) and cellular (electrophysiology) levels to observed clinical effects in living patients. Glutamatergic neurons derived from schizophrenia patients exhibited deficits in intrinsic electrophysiological properties, synaptic function and network activity. Deficits in K+ and Na+ currents, network behavior, and glutamatergic synaptic signaling were restored by clozapine treatment, but only in neurons from clozapine-responsive patients. Moreover, neurons from clozapine-responsive patients exhibited a reciprocal dysregulation of gene expression, particularly related to glutamatergic and downstream signaling, which was reversed by clozapine treatment. Only neurons from clozapine responders showed return to normal function and transcriptomic profile. Our results underscore the importance of K+ and Na+ channels and glutamatergic synaptic signaling in the pathogenesis of schizophrenia and demonstrate that clozapine might act by normalizing perturbances in this signaling pathway. To our knowledge this is the first study to demonstrate that schizophrenia iPSC-derived neurons exhibit a response phenotype correlated with clinical response to an antipsychotic. This opens a new avenue in the search for an effective treatment agent tailored to the needs of individual patients.

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“…Rather, the CA4 subfield is most altered [ 73 , 74 ]. A recent RNAseq analysis in the postmortem hippocampus showed a subfield-specific molecular profile pattern in the DG, CA3, and CA1 subfields of schizophrenia patients when compared to controls [ 80 ]. Taken together with the volume and neuronal morphometry studies analyzed in our current study, postmortem studies indicate regional heterogeneity in schizophrenia pathology.…”

Section: Discussionmentioning

confidence: 99%

Hippocampal volume and hippocampal neuron density, number and size in schizophrenia: a systematic review and meta-analysis of postmortem studies

et al. 2020

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Reduced hippocampal volume is a consistent finding in neuroimaging studies of individuals with schizophrenia. While these studies have the advantage of large sample sizes, they are unable to quantify the cellular basis of structural or functional changes. In contrast, postmortem studies are well suited to explore subfield and cellular alterations, but low sample sizes and subject heterogeneity impede establishment of statistically significant differences. Here we use a meta-analytic approach to synthesize the extant literature of hippocampal subfield volume and cellular composition in schizophrenia patients and healthy control subjects. Following pre-registration (PROSPERO CRD42019138280), PubMed, Web of Science, and PsycINFO were searched using the term: (schizophrenia OR schizoaffective) AND (post-mortem OR postmortem) AND hippocampus. Subjects were adult men and women with schizophrenia or schizoaffective disorder or non-psychiatric control subjects, and key outcomes, stratified by hippocampal hemisphere and subfield, were volume, neuron number, neuron density, and neuron size. A random effects meta-analysis was performed. Thirty-two studies were included (413 patients, 415 controls). In patients, volume and neuron number were significantly reduced in multiple hippocampal subfields in left, but not right hippocampus, whereas neuron density was not significantly different in any hippocampal subfield. Neuron size, averaged bilaterally, was also significantly reduced in all calculated subfields. Heterogeneity was minimal to moderate, with rare evidence of publication bias. Meta-regression of age and illness duration did not explain heterogeneity of total hippocampal volume effect sizes. These results extend neuroimaging findings of smaller hippocampal volume in schizophrenia patients and further our understanding of regional and cellular neuropathology in schizophrenia.

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Hippocampal subfield transcriptome analysis in schizophrenia psychosis

Cited by 29 publications

References 76 publications

Resolving cellular and molecular diversity along the hippocampal anterior-to-posterior axis in humans

Resolving cellular and molecular diversity along the hippocampal anterior-to-posterior axis in humans

Clozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive Schizophrenia Patients

Hippocampal volume and hippocampal neuron density, number and size in schizophrenia: a systematic review and meta-analysis of postmortem studies

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