Akt and AMPK activators rescue hyperexcitability in neurons from patients with bipolar disorder.
Level 5 - mechanism / opinion, no new human data
In vitro laboratory study using human iPSC-derived neurons.
PubMed 38772282 · doi:10.1016/j.ebiom.2024.105161
What was done
Induced pluripotent stem cell-derived neurons were generated from patients with bipolar disorder classified as lithium-responsive or lithium-non-responsive. Investigators evaluated neuronal hyperactivity and the mechanisms of lithium action using electrophysiology, calcium imaging, biochemistry, whole transcriptome sequencing, and phosphoproteomics, and tested the effects of Akt and AMPK activators.
What was found
Lithium selectively rescued the neuronal hyperactivity phenotype in lithium-responsive neurons, which correlated with changes in sodium conductance. Whole transcriptome sequencing revealed altered gene expression pathways related to glutamate transmission, cell signaling, and ion transport or channel activity. Akt signaling was altered in lithium-responsive neurons, and pharmacologic Akt activation mimicked the effect of lithium in these cells. AMPK activation reversed increased neural network activity in both lithium-responsive and lithium-non-responsive neurons. The abstract reports no quantitative values or statistical metrics.
Why it matters
This work identifies cellular mechanisms underlying differential lithium responsiveness in bipolar disorder and points to Akt and AMPK activators as potential therapeutic strategies for lithium-responsive and lithium-resistant cases, respectively.
Limits
The study is an in vitro model using cultured stem cell-derived neurons, which cannot capture intact human brain circuitry or clinical efficacy. The abstract omits the number of patient donors, cell lines, and biological replicates, and reports no numerical data.
Cited by
- supports Martin Alda and his research team found that lithium modulates the insulin signaling pathway in brain organoids derived from bipolar disorder patient neurons.