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A Co-Culture Model of Dopaminergic and Glutamatergic Neurons Derived from Patients with Idiopathic Schizophrenia reveals a Hypodopaminergic Phenotype

ABSTRACT: A Co-Culture Model of Dopaminergic and Glutamatergic Neurons Derived from Patients with Idiopathic Schizophrenia reveals a Hypodopaminergic Phenotype

PROVIDER: PRJNA1149033 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30275671_1.fastq.gz	Fastqsanger.gz
	SRR30275671_2.fastq.gz	Fastqsanger.gz
	SRR30275672_1.fastq.gz	Fastqsanger.gz
	SRR30275672_2.fastq.gz	Fastqsanger.gz
	SRR30275673_1.fastq.gz	Fastqsanger.gz

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A Co-Culture Model of Dopaminergic and Glutamatergic Neurons Derived from Patients with Idiopathic Schizophrenia reveals a Hypodopaminergic Phenotype

Project description:To identify morphological and functional phenotypes relevant for SCZ, we generated iPSC-derived dopaminergic neurons from three healthy controls and four patient with schizophrenia. We then performed gene expression profiling analysis using data obtained from RNA-seq of four schizophrenia patients and three controls to determine significantly deregulated genes in schizophrenia dopaminergic neurons.

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Project description:Schizophrenia (SCZ) is a psychiatric disorder with a strong genetic determinant. A major hypothesis to explain disease aetiology comprises synaptic dysfunction associated with excitatory-inhibitory imbalance of synaptic transmission, ultimately contributing to impaired network oscillation and cognitive deficits associated with the disease. Here, we studied the morphological and functional properties of a highly defined co-culture of GABAergic and glutamatergic neurons derived from induced pluripotent stem cells (iPSC) from patients with idiopathic SCZ. Our results indicate upregulation of synaptic genes and increased excitatory synapse formation on GABAergic neurons in co-cultures. In parallel, we observed decreased lengths of axon initial segments, concordant with data from postmortem brains from patients with SCZ. Patch-clamp analyses revealed differential processing of excitatory input with markedly increased spontaneous excitatory postsynaptic currents (EPSC) recorded from GABAergic SCZ neurons and decreased spontaneous EPSC from glutamatergic SCZ neurons. Likewise, we observed decreased amplitudes of calcium signals selectively in GABAergic neurons while frequency was increased in both neuronal populations. Finally, MEA recordings from neuronal networks indicate increased synchronization of network activity. In conclusion, our results suggest selective deregulation of neuronal activity and synaptic transmission in SCZ samples, providing evidence for differential signal processing in GABAergic and glutamatergic neurons as a potential base for aberrant network synchronization.

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Common schizophrenia risk variants are implicated in the function of glutamatergic neurons

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