Thursday, 8 June 2017

Neto2 and Autism

Today's brief post should be good for our Canadian reader AJ.  It looks like there are clever researchers close by at the Weston Brain Institute, in Toronto. It is indeed a small world because many years ago I worked in Australia in a small company with one of the same Westons, who by coincidence is now the boss of the large UK company, I earlier worked for as a student and the Westons subsequently bought.
There are two Weston foundations, one in Canada and one in England, together with assets of a few billion dollars/pounds/euros.  One of their areas of interest is neuroscience.
One of the Toronto Weston Brain Institute’s researchers wrote her PhD thesis on an aspect I skipped over in my previous already complex post on KCC2, the role of Neto2. She also knows about neuroligin2 (NL2).  Here is her PhD thesis:- 

So what would be nice would be to apply some Weston brain/financial capacity to figure out how to upregulate KCC2, via Neto2, or indeed any other mechanism.
The science, in summary, is that the protein Neto2 is required for the KCC2 cotransporter to be present and potentially if you increase the expression of Neto2 you might well increase the expression of KCC2 and so help shift immature neurons towards mature neurons.  

The mechanisms that regulate the activity of the neuron specific K+Cl- cotransporter (KCC2) remain poorly understood, despite the critical importance of this transporter in inhibitory synaptic transmission and plasticity. In this thesis I describe three novel discoveries which reveal the cellular and molecular mechanisms of KCC2 regulation.  First, I assayed the K+Cl- cotransport function of KCC2 under isotonic conditions and determined the molecular domain of the cotransporter required for constitutive Cl- transport in hippocampal neurons (Acton et al 2012).   Specifically, I identified the 15 amino acid domain of the C-terminus in neurons that is responsible for the ability of KCC2 to cotransport K+Cl- under basal isotonic conditions, allowing it to remain constitutively active to create the steep Cl- gradient across the neuronal membrane required for synaptic inhibition. Secondly, I investigated a novel KCC2-interacting protein named Neto2 and determined its effect on the postsynaptic action of GABA (Ivakine et al 2013). I have found that Neto2, which is also an auxiliary protein of kainate-type ionotropic receptors, can also regulate the activity of the KCC2.  Neto2 is required for neurons to maintain low [Cl-]i and strong synaptic inhibition.  Third, I examined the functional relevance of the KCC2:Neto2:KAR multiprotein complex and found that this complex regulates the surface level membrane expression pattern of KCC2 and the stability of the cotransporter in the membrane.

Moreover, I have provided the first evidence that the interactions of KCC2:Neto2:GluK2 regulate KCC2 via a PKC-mediated phosphorylation of the cotransporter. Taken together, these results resolve three novel mechanisms of KCC2 regulation: the identity of the key C-terminal domain of KCC2 required for isotonic transport, the functional significance of the KCC2:Neto2 interaction, and the potential mechanisms by which the KCC2:Neto2:KAR complex regulates KCC2 expression and mobility in the neuronal membrane.


  1. I live in Toronto.
    But can't open the link to thesis paper.

    1. Debbie, try the link again. I think it is their security software. If it still does not work go to google and enter:-

      Mechanisms of Inhibitory Synaptic Plasticity: the Regulation of KCC2

      Click on the link to the pdf file.

    2. Debbie there is also lab within the University of Toronto focused on this very subject:-

      Melanie A. Woodin is an Associate Professor in the Department of Cell and Systems Biology at the University of Toronto and a Director of the Human Biology Program. Her lab focuses on the regulation of neuronal chloride transporter KCC2, GABAergic synaptic transmission and inhibitory synaptic plasticity in the hippocampus.

  2. Hi Peter,

    Thanks for this article! I had no idea about the Weston Brain Institute, nor the work that is specifically going on at U of T. A lab that focuses on the regulation of neuronal chloride transporter KCC2, GABAergic synaptic transmission and inhibitory synaptic plasticity in the hippocampus is pretty ideal.

    U of T is one of the best Universities in Canada (we have many excellent universities) and I'm glad to see the nature of work being done there.

    We really do have some great researchers doing good work here in Canada like Dr. Stephen Scherer (who was very kind to me when I reached out to him about getting my daughter's genetics tested as part of his program) at Sick Kids Hospital and Dr. Evdokia Anagnostou at Holland Bloorview.

    I believe they are also doing some good work at McMaster University ( ) and I'm sure at all of our great universities and hospitals.

    The recent news about Metformin and autism was out of McGill University (with the University of Montreal):


    1. AJ, it remarkable how much autism research goes on in Canada, both very scientific and more "trial and error" clinical trials. You have to wonder why much larger, developed countries do virtually none (Germany, UK etc).

  3. Hi Peter,

    I agree 100%. Imagine how much further we would be if many other developed countries put in the same amount of research we (the US and Canada) do on ASD.

    Speaking of putting money into ASD, I have to say, I'm very proud of my province of Ontario for the following which just came out:

    We just put out a press release confirming that we (Ontario) are putting in $500 million towards services for kids with autism. We already had good services but now we're putting in a ton more money to help kids up until age 18.

    As a taxpayer, there are lots of things I think our governments waste money on, but I am really proud and pleased to see my government apply so much money to what I have learned is such a worthy cause.

    Have a great day!



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