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December 21, 2006



If one was to look at the relationship of Bipolar Disorder to its frequent comorbidites, perhaps cl- transport would be the best place to start. IMHO persistent up regulation of NKCC1 would depolarize GABA responses and at the same time effect Mucus transport, pain signalling etc.. Also interesting is the possible connection to the post you made about accutane and depression. Trkb is up-regulated by retinoic acid, which in-turn controls NKCC1 and KCC2.


Richard Petty

Dear Glen,

Chloride transport is indeed one of the candidates. Others are the serotonin transporter (I wrote a short piece about that here: and yet another moves away form receptors to the cell membrane itself. There is some evidence for disturbed phospholipase A2 activity. There are a few references here:

I like your line of reasoning. I know several world class psychopharmacolgists who have been thinking along similar lines. Most are out of town for the next couple of weeks, but I am going to shoot off a few email and see where their work has gone over the last few months since we last talked.

If they have any new material in the public domain I shall post it.

Kind regards,



Hello Dr. Petty,

In my brevity I perhaps gave a wrong impression. I did not mean to imply that Cl- transport is solely responsible for BD. While certainly possible, I posit that any of the suspected or implicated genetic (or environmental) factors will lead to and up-regulation of NKCC1 and corresponding down regulation of KCC2. With so many links in the chain of neural plasticity, the disruption of any one of them (BDNF, NGF, serotonin, mitochondrial function, etc.) will lead to an eventual up/down regulation of NKCC1/KCC2. And seeing that NKCC1 is also expressed outside of the brain also (unlike KCC2) the implications of such should manifest themselves throughout the body. Another example of where this relationship to Cl- may be a factor is in Fibromagilia and Neuropathic pain. Links;

Richard Petty

Dear Glen,

Thank you very much for clarifying your point.

I could see your reasoning, but for people less familar wih the field, I think that it was extremely useful for you to flesh out your ideas in more detail.

Thank you also for adding the links.

Kind regards,



Hello again Dr. Petty,

First off I love the blog!

I recent paper by Dr.De Koninck is perhaps the best summation of the issue. The only omission/oversight I could see in it is the oft reported BDNF triggered rise in cl- via trkb, is the mentioned without note to the possibility of the cl- rise being based on activity. Dr. Claudio Rivera has (IMO) done the best work in this regard, showing that activity leads to a down-regulation of KCC2 (also via trkb).


Richard Petty

Dear Glen,

Thank you for the kind comment about the blog, and also for the link.

I had not seen the De Koninck paper, and I am asking one of our researchers to get me a copy of the whole paper.

Kind regards,


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