Elucidating the Neural Basis of Bipolar Disorder - Secondary Publication.

Bipolar disorder is a mental disorder characterized by recurrent episodes of mania/hypomania and depression, with a strong genetic contribution and substantial functional burden. Recent genomic studies implicate multiple risk variants converging on intracellular calcium (Ca2+) signaling and synaptic function, while neurons derived from induced pluripotent stem cells of patients with bipolar disorder demonstrate altered neuronal excitability and lithium-responsive phenotypes. Building on early neuroimaging and postmortem observations, accumulating evidence supports the mitochondrial dysfunction hypothesis, which proposes that impaired mitochondrial Ca2+ buffering disrupts neuronal Ca2+ homeostasis and contributes to mood instability. Diverse findings align with this framework: altered brain energy metabolism, increased mitochondrial DNA (mtDNA) deletions, elevated lactate, reduced mitochondrial gene expression and complex I proteins, enrichment of deleterious de novo and mosaic variants in Ca2+ signaling- and mitochondrial/endoplasmic reticulum-related genes, and a higher prevalence of the MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)-associated m.3243A>G mutation in individuals with bipolar disorder. Animal models further strengthen causal inference. Neuron-specific Ant1 knockout mice exhibit reduced mitochondrial Ca2+ uptake and serotonergic hyperexcitability, while mice with neuron-specific mutant Polg accumulate mtDNA deletions and show recurrent depression-like episodes responsive to lithium and switch-like manic behaviors following treatment with a tricyclic antidepressant, indicating construct, face, and predictive validity. To identify the critical brain substrate, mtDNA deletions were mapped and found to accumulate most prominently in the paraventricular thalamic nucleus (PVT), a serotonergic-recipient hub projecting to limbic circuits involved in emotional salience. Human postmortem single-nucleus analyses reveal marked reductions of PVT neurons and prominent gene expression changes in the PVT, including enrichment of GWAS (genome-wide association study) signals among downregulated genes, as well as neuropathological alterations such as granulovacuolar degeneration in the PVT in late-onset cases. These convergent data suggest that genetically driven Ca2+ dysregulation and mitochondrial vulnerability promote circuit-level dysfunction-particularly within the serotonin-PVT-limbic pathway-leading to dysregulated emotion-cognition balance and mood swings.