Human stem cell-based models to study synaptic dysfunction and cognition in schizophrenia: A narrative review

Santarriaga, Stephanie; Gerlovin, Kaia; Layadi, Yasmine; Karmacharya, Rakesh

doi:10.1016/j.schres.2023.02.029

Cited by 2 publications

(2 citation statements)

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“…PET imaging revealed that synaptic vesicle glycoprotein 2A, widely expressed in presynaptic terminals and synaptic vesicles, was reduced in different brain regions in SZ, and was associated with either positive or cognitive symptoms (Onwordi et al, 2021;Radhakrishnan et al, 2021). Post-mortem and GWAS findings were confirmed by transcriptomic and proteomic data obtained from patient-derived induced pluripotent stem cells (Santarriaga et al, 2023).…”

Section: Abnormal Synaptic Plasticitymentioning

confidence: 75%

New clues for the role of cerebellum in schizophrenia and the associated cognitive impairment

Faris,

Pischedda,

Palesi

et al. 2024

Front. Cell. Neurosci.

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Schizophrenia (SZ) is a complex neuropsychiatric disorder associated with severe cognitive dysfunction. Although research has mainly focused on forebrain abnormalities, emerging results support the involvement of the cerebellum in SZ physiopathology, particularly in Cognitive Impairment Associated with SZ (CIAS). Besides its role in motor learning and control, the cerebellum is implicated in cognition and emotion. Recent research suggests that structural and functional changes in the cerebellum are linked to deficits in various cognitive domains including attention, working memory, and decision-making. Moreover, cerebellar dysfunction is related to altered cerebellar circuit activities and connectivity with brain regions associated with cognitive processing. This review delves into the role of the cerebellum in CIAS. We initially consider the major forebrain alterations in CIAS, addressing impairments in neurotransmitter systems, synaptic plasticity, and connectivity. We then focus on recent findings showing that several mechanisms are also altered in the cerebellum and that cerebellar communication with the forebrain is impaired. This evidence implicates the cerebellum as a key component of circuits underpinning CIAS physiopathology. Further studies addressing cerebellar involvement in SZ and CIAS are warranted and might open new perspectives toward understanding the physiopathology and effective treatment of these disorders.

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Section: Abnormal Synaptic Plasticitymentioning

confidence: 75%

New clues for the role of cerebellum in schizophrenia and the associated cognitive impairment

Faris,

Pischedda,

Palesi

et al. 2024

Front. Cell. Neurosci.

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“…The ability to generate iPSCs from well-characterized schizophrenia patients and healthy subjects enables us to generate neuronal cells that have the same genetic background as the subjects and interrogate biological differences that result from the collective effect of the complex genetic backgrounds [58][59][60][61][62]. There is convergent data, including from iPSCbased studies, that implicate deficits in synaptic biology in the etiopathogenesis of schizophrenia [63][64][65]. Schizophrenia is typically diagnosed in adolescence or early adulthood [66].…”

Section: Discussionmentioning

confidence: 99%

Morphological and transcriptomic analyses of stem cell-derived cortical neurons reveal mechanisms underlying synaptic dysfunction in schizophrenia

et al. 2023

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Background Postmortem studies in schizophrenia consistently show reduced dendritic spines in the cerebral cortex but the mechanistic underpinnings of these deficits remain unknown. Recent genome-wide association studies and exome sequencing investigations implicate synaptic genes and processes in the disease biology of schizophrenia. Methods We generated human cortical pyramidal neurons by differentiating iPSCs of seven schizophrenia patients and seven healthy subjects, quantified dendritic spines and synapses in different cortical neuron subtypes, and carried out transcriptomic studies to identify differentially regulated genes and aberrant cellular processes in schizophrenia. Results Cortical neurons expressing layer III marker CUX1, but not those expressing layer V marker CTIP2, showed significant reduction in dendritic spine density in schizophrenia, mirroring findings in postmortem studies. Transcriptomic experiments in iPSC-derived cortical neurons showed that differentially expressed genes in schizophrenia were enriched for genes implicated in schizophrenia in genome-wide association and exome sequencing studies. Moreover, most of the differentially expressed genes implicated in schizophrenia genetic studies had lower expression levels in schizophrenia cortical neurons. Network analysis of differentially expressed genes led to identification of NRXN3 as a hub gene, and follow-up experiments showed specific reduction of the NRXN3 204 isoform in schizophrenia neurons. Furthermore, overexpression of the NRXN3 204 isoform in schizophrenia neurons rescued the spine and synapse deficits in the cortical neurons while knockdown of NRXN3 204 in healthy neurons phenocopied spine and synapse deficits seen in schizophrenia cortical neurons. The antipsychotic clozapine increased expression of the NRXN3 204 isoform in schizophrenia cortical neurons and rescued the spine and synapse density deficits. Conclusions Taken together, our findings in iPSC-derived cortical neurons recapitulate cell type-specific findings in postmortem studies in schizophrenia and have led to the identification of a specific isoform of NRXN3 that modulates synaptic deficits in schizophrenia neurons.

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Human stem cell-based models to study synaptic dysfunction and cognition in schizophrenia: A narrative review

Cited by 2 publications

References 324 publications

New clues for the role of cerebellum in schizophrenia and the associated cognitive impairment

New clues for the role of cerebellum in schizophrenia and the associated cognitive impairment

Morphological and transcriptomic analyses of stem cell-derived cortical neurons reveal mechanisms underlying synaptic dysfunction in schizophrenia

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