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Dysfunction of cAMP-Protein Kinase A-calcium signaling axis in striatal medium spiny neurons: a role in schizophrenia and Huntington’s disease neuropathology

Fjodorova, Marija, Noakes, Zoe ORCID:, Cabezas De La Fuente, Daniel, Errington, Adam ORCID: and Li, Meng ORCID: 2023. Dysfunction of cAMP-Protein Kinase A-calcium signaling axis in striatal medium spiny neurons: a role in schizophrenia and Huntington’s disease neuropathology. Biological Psychiatry: Global Open Science 3 (3) , pp. 418-429. 10.1016/j.bpsgos.2022.03.010

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Background Striatal medium spiny neurons (MSNs) are preferentially lost in Huntington’s disease. Genomic studies also implicate a direct role for MSNs in schizophrenia, a psychiatric disorder known to involve cortical neuron dysfunction. It remains unknown whether the two diseases share similar MSN pathogenesis or if neuronal deficits can be attributed to cell type–dependent biological pathways. Transcription factor BCL11B, which is expressed by all MSNs and deep layer cortical neurons, was recently proposed to drive selective neurodegeneration in Huntington’s disease and identified as a candidate risk gene in schizophrenia. Methods Using human stem cell–derived neurons lacking BCL11B as a model, we investigated cellular pathology in MSNs and cortical neurons in the context of these disorders. Integrative analyses between differentially expressed transcripts and published genome-wide association study datasets identified cell type–specific disease-related phenotypes. Results We uncover a role for BCL11B in calcium homeostasis in both neuronal types, while deficits in mitochondrial function and PKA (protein kinase A)–dependent calcium transients are detected only in MSNs. Moreover, BCL11B-deficient MSNs display abnormal responses to glutamate and fail to integrate dopaminergic and glutamatergic stimulation, a key feature of striatal neurons in vivo. Gene enrichment analysis reveals overrepresentation of disorder risk genes among BCL11B-regulated pathways, primarily relating to cAMP-PKA-calcium signaling axis and synaptic signaling. Conclusions Our study indicates that Huntington’s disease and schizophrenia are likely to share neuronal pathophysiology where dysregulation of intracellular calcium homeostasis is found in both striatal and cortical neurons. In contrast, reduction in PKA signaling and abnormal dopamine/glutamate receptor signaling is largely specific to MSNs.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Advanced Research Computing @ Cardiff (ARCCA)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Publisher: Elsevier
ISSN: 2667-1743
Funders: MRC
Date of First Compliant Deposit: 29 March 2022
Date of Acceptance: 22 March 2022
Last Modified: 11 Jun 2024 15:23

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