Multi-scale investigation of cellular and molecular patterns in schizophrenia
Tyler Teadora
János Szentágothai Neurosciences
Dr. Bereczki Dániel
SE Neurológiai és Pszichiátriai Klinika közös tanterme
2025-09-24 14:00:00
Neuromorphology and cell biology
Dr. Alpár Alán
Dr. Adorján István
Dr. Maglóczky Zsófia
Dr. Pircs Karolina
Dr. Réthelyi János
Dr. Zachar Gergely
Dr. Dávid Csaba
Dr. Szebényi Kornélia
Schizophrenia (SCH) is a devastating neuropsychiatric disorder with poorly understood etiology. Despite extensive research, literature regarding underlying cell-type-specific alterations in SCH remains controversial. Here, we applied quantitative immunohistochemistry to measure the relative density of certain cell types in the dorsolateral prefrontal cortex (DLPFC) and the caudate nucleus (CN); single nucleus RNA sequencing to measure cell type specific gene expression in the DLPFC; and in situ mRNA hybridization to validate differentially expressed genes and further examine protein- and mRNA expression patterns in the DLPFC.
The density of calretinin-expressing (CR) interneurons was lower in the CN and in cortical layer 2 of the DLPFC, which was not influenced by known confounder factors. Single nucleus RNA sequencing conducted on a sample cohort overlapping with the cohort used for histology revealed network-level dysfunction in various excitatory and inhibitory cell types mostly localized to upper cortical layers. Cell types demonstrating the most profound disturbance involved transcriptomic subtypes of somatostatin, parvalbumin, and CR inhibitory neurons, and various excitatory neuron types. Pathway analyses of differentially expressed genes suggested disturbance in energy metabolism, protein biogenesis and localization primarily in inhibitory interneurons, while genes disturbed in excitatory neuron types were rather associated with neurotransmission- and development-related pathways.
Because the sequencing did not reveal significantly lower calretinin mRNA levels in SCH, we applied in situ mRNA hybridization with immune co-detection to simultaneously assess CR protein and mRNA levels (n = 5 CTR/5 SCH). The results indicated disrupted CR protein translation in SCH, with a higher proportion of neurons expressing calretinin mRNA without the protein.
Together, our results suggest that CR protein expression may be affected in SCH, which, seeing its important role in calcium buffering and calcium signalling, could contribute to disrupted neurotransmission. The presented evidence is intriguing, albeit modest: it underlines the need for better understanding of the neurochemical and functional properties of human cortical and striatal CR interneurons in both healthy and pathological conditions.
