Yoon et al., Proceedings of the National Academy of Sciences - ANK3, which encodes the scaffolding protein ankyrin-G, is a major risk gene for bipolar disorder and schizophrenia, yet what it does in adult neurons has been unclear. This study deletes Ank3 from mouse forebrain excitatory neurons either before birth or from adolescence and finds a convergent adult profile: hyperactivity and less anxiety-like and depression-like behavior, with social behavior intact. The neurons become less active, their membrane proteome shifts, and myelin basic protein falls, a protein made by oligodendrocytes rather than by the neurons that lost Ank3. Key terms: ANK3, ankyrin-G, bipolar disorder, myelin basic protein, lithium.
Study Highlights:
Deleting Ank3 prenatally with Emx1-Cre or from adolescence with CaMKIIα-Cre produced convergent adult phenotypes, including hyperactivity, reduced anxiety-like behavior and reduced immobility in the forced swim test, while the three-chamber social test was normal in both lines. Calcium imaging showed that ankyrin-G knockdown lowered spontaneous activity in cultured cortical neurons and that knockout slices gave smaller KCl-evoked calcium responses in layer 2/3 of somatosensory cortex. Quantitative TMT proteomics of the cortical membrane fraction quantified 2,357 proteins, of which 75 changed, 59 up and 16 down, and western blots confirmed higher Ryr2 and Taok2 and lower myelin basic protein. Mbp immunostaining was reduced in cortical layers 2/3 and 4 but not in layer 5 or hippocampal CA3, and myelin sheath diameter did not change significantly. A three-week lithium diet restored Mbp in the P3 fraction but not in the P2 membrane fraction, and left Ryr2 and Taok2 unchanged.
Conclusion:
Removing ankyrin-G from adult excitatory neurons is enough to produce hyperactive, low-anxiety mice with quieter neurons and less myelin basic protein, which ties a psychiatric risk gene in neurons to a myelin-associated protein made by glia. Lithium's selective restoration of Mbp suggests one possible myelin-related component of its action, although the cellular source of the Mbp change and any structural myelin deficit remain to be shown.
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Article title:
Ank3 loss in adult forebrain excitatory neurons disrupts behavior, neuronal activity, membrane proteome, and myelination
First author:
Yoon
Journal:
Proceedings of the National Academy of Sciences
DOI:
10.1073/pnas.2606900123
Reference:
Yoon, S., Dos Santos, M., Khalatyan, N., Savas, J.N., and Penzes, P. (2026). Ank3 loss in adult forebrain excitatory neurons disrupts behavior, neuronal activity, membrane proteome, and myelination. Proceedings of the National Academy of Sciences 123(35), e2606900123. https://doi.org/10.1073/pnas.2606900123
License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
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This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-09-24.
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Chapters
- (00:00:20) - Introduction: The hyperactivity paradox
- (00:02:02) - Meet ANK3 and ankyrin G's structural role
- (00:03:52) - Mouse model design: timing the gene deletion
- (00:06:19) - Behavioral tests: hyperactivity and reduced anxiety
- (00:08:34) - Calcium imaging reveals quiet neurons
- (00:10:17) - Proteomics: widespread molecular remodeling
- (00:12:09) - The myelin basic protein surprise
- (00:13:57) - Localizing the MBP deficit in the cortex
- (00:14:36) - Lithium treatment and the P2 fraction results
- (00:16:10) - Lithium's precise rescue in the synaptic P3 fraction
- (00:17:08) - Hypothesis: axoglial signaling breakdown
- (00:18:28) - Rethinking how mood stabilizers work
- (00:19:17) - Limitations and study boundaries
- (00:20:06) - Summary and implications for future treatment
- (00:20:43) - Closing and credits
- (00:21:57) - Original inspired track
