Disturbances of paraventricular thalamic nucleus neurons in bipolar disorder revealed by single-nucleus analysis

TL;DR

This study identifies significant changes in paraventricular thalamic neurons in bipolar disorder patients, suggesting a key role in the disease's pathology.

Contribution

The study reveals novel transcriptional abnormalities in the paraventricular thalamic nucleus specific to bipolar disorder.

Findings

PVT neurons showed the largest number of differentially expressed genes and a ~50% reduction in cell count in BD patients.

Synaptic and ion channel-related genes like SHISA9, CACNA1C, and KCNQ3 were significantly downregulated in BD PVT neurons.

Disrupted interactions between thalamic excitatory neurons and microglia were observed in bipolar disorder.

Abstract

Bipolar disorder (BD) is a major global health burden, and its treatment challenges highlight the need for pathology-based therapeutic development. Emerging evidence suggests that the thalamus, particularly the paraventricular thalamic nucleus (PVT), is a key region in mood regulation. We performed single-nucleus RNA sequencing on 82 thalamic and cortical samples from 21 patients with BD and 20 controls to compare transcriptional pathology. PVT neurons showed the most striking abnormalities, including the largest number of differentially expressed genes and ~50% fewer cells in BD, whereas cortical alterations were comparatively modest. PVT neurons exhibited marked downregulation of synaptic and ion channel-related genes such as SHISA9, CACNA1C, and KCNQ3, which are linked to BD risk and serve as central nodes in downregulated networks. We also observed disrupted interactions between thalamic excitatory neurons and microglia. Overall, PVT neurons emerge as a central pathological substrate and a promising diagnostic and therapeutic target in BD.

The pathological mechanisms of bipolar disorder remain largely unknown. Here, authors show marked loss and synaptic gene disruption in paraventricular thalamic neurons by single-nucleus analysis of human brains, highlighting this deep-brain region.

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