Excellent read, thank you! Regarding the correlations observed between ADHD and bipolar you mention specifically, I thought there had been robust enough genetic findings regarding COMT gene expression, and its most well-known mutations (fast and low COMT vs. "normal" COMT), to support this? The associated phenotypes clearly underpin the aforementioned correlations (as well as any you mention that involve dopamine dysregulation, potentially). Again, not the whole picture, but an important piece perhaps?
Thanks so much for your comment. These are good questions. My understanding is that genetic mapping hasn’t been particularly kind to the COMT story. It’s a mechanistic story that was popular many years ago but didn’t find much genetic support so the overlap you’re pointing out probably has a much more polygenic explanation. My sense is that for some ADHD and bipolar patients, susceptibility to dopaminergic actuators is a mechanistic convergence that doesn’t necessarily require a dopaminergic genetic cause (e.g. could be indirect ways in which many things change and dopamine just happens to be a vulnerable node)
Oh, I see! Interesting, I wasn't aware of the fall from grace of the COMT theory. It'd be really interesting to find out more about different paths to mechanistic convergence from a genetic or gene/environment correlation standpoint, as the E/I framework is a system-based one that (probably?) exists downstream from something else. I understand this is kind of the point of research at the moment, just too many questions. Thanks so much for taking the time, and of course, for the work itself!
Whats your take on the correlations between immune activation and schizophrenia. For example pro-inflammatory markers are correlated with symptom severity. And genetic varation in the complement pathway is a predictor of risk.
One idea out there is that kyneurnic acid is a link. Its an NMDA antagonist and its generated in peripheral tissues in large quantities by immune cells.
We're far off from using cell replacement therapy in the brain but the immune system is already being modified in the clinic. This opens up synthetic biology based approaches.
Thanks for your comments. The C4 findings are interesting genetic discoveries in schizophrenia and point toward synaptic pruning during adolescent development as a potential mechanism. The kynurenic acid hypothesis is interesting because it could bridge peripheral immune activation to the prefrontal E/I story, but it will need to be tested rigorously. I know some companies are developing drugs in that space so we will see where it goes. Thanks again
Thank you Dr. Halassa. As a layperson I've been interested in schizophrenia since I read Philippe Frossard's "The Lottery of Life" about thirty years ago. It's disappointing that little progress has been made on the hereditary factors, although Frossard warned that schizophrenia is a group of diseases, heterogeneous, and thus it is extremely difficult to determine even on which chromosome the genes reside, for each different type of schizophrenia! Researching it must be like making your way across a minefield, blindfolded, on a moonless night. Respect.
Excellent read, thank you! Regarding the correlations observed between ADHD and bipolar you mention specifically, I thought there had been robust enough genetic findings regarding COMT gene expression, and its most well-known mutations (fast and low COMT vs. "normal" COMT), to support this? The associated phenotypes clearly underpin the aforementioned correlations (as well as any you mention that involve dopamine dysregulation, potentially). Again, not the whole picture, but an important piece perhaps?
Thanks so much for your comment. These are good questions. My understanding is that genetic mapping hasn’t been particularly kind to the COMT story. It’s a mechanistic story that was popular many years ago but didn’t find much genetic support so the overlap you’re pointing out probably has a much more polygenic explanation. My sense is that for some ADHD and bipolar patients, susceptibility to dopaminergic actuators is a mechanistic convergence that doesn’t necessarily require a dopaminergic genetic cause (e.g. could be indirect ways in which many things change and dopamine just happens to be a vulnerable node)
Oh, I see! Interesting, I wasn't aware of the fall from grace of the COMT theory. It'd be really interesting to find out more about different paths to mechanistic convergence from a genetic or gene/environment correlation standpoint, as the E/I framework is a system-based one that (probably?) exists downstream from something else. I understand this is kind of the point of research at the moment, just too many questions. Thanks so much for taking the time, and of course, for the work itself!
Exactly! Thanks for your engagement.
Great read and somehow hopeful!
Whats your take on the correlations between immune activation and schizophrenia. For example pro-inflammatory markers are correlated with symptom severity. And genetic varation in the complement pathway is a predictor of risk.
One idea out there is that kyneurnic acid is a link. Its an NMDA antagonist and its generated in peripheral tissues in large quantities by immune cells.
We're far off from using cell replacement therapy in the brain but the immune system is already being modified in the clinic. This opens up synthetic biology based approaches.
Thanks for your comments. The C4 findings are interesting genetic discoveries in schizophrenia and point toward synaptic pruning during adolescent development as a potential mechanism. The kynurenic acid hypothesis is interesting because it could bridge peripheral immune activation to the prefrontal E/I story, but it will need to be tested rigorously. I know some companies are developing drugs in that space so we will see where it goes. Thanks again
Thank you Dr. Halassa. As a layperson I've been interested in schizophrenia since I read Philippe Frossard's "The Lottery of Life" about thirty years ago. It's disappointing that little progress has been made on the hereditary factors, although Frossard warned that schizophrenia is a group of diseases, heterogeneous, and thus it is extremely difficult to determine even on which chromosome the genes reside, for each different type of schizophrenia! Researching it must be like making your way across a minefield, blindfolded, on a moonless night. Respect.
Thank you! Very kind of you to say so. Yep, feels like way much of the time but that’s the story of humanity!