Canonical Wnt3a modulates intracellular calcium and enhances excitatory neurotransmission in hippocampal neurons
Authors: Luis G Aguayo
Miguel E Avila
Giancarlo V De Ferrari
Randall T Moon
Carlos F Burgos
Fernando J Sepúlveda
Gustavo Moraga-Cid
Carlos Opazo
Jorge Parodi
Journal: Journal of Biological Chemistry (2010)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Wnt signal transduction; brain structures; synaptic plasticity; neurotransmission; Wnt protein
Affiliations: Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Universidad de Concepción, PO Box 4070386, Concepción, Chile.

Abstract:  A role for Wnt signal transduction in the development and maintenance of brain structures is widely acknowledged. Recent studies have suggested that Wnt signaling may be essential for synaptic plasticity and neurotransmission. However, the direct effect of a Wnt protein on synaptic transmission had not been demonstrated. Here we show that nanomolar concentrations of purified Wnt3a protein rapidly increase the frequency of miniature excitatory synaptic currents in embryonic rat hippocampal neurons through a mechanism involving a fast influx of calcium from the extracellular space, induction of post-translational modifications on the machinery involved in vesicle exocytosis in the presynaptic terminal leading to spontaneous Ca(2+) transients. Our results identify the Wnt3a protein and a member of its complex receptor at the membrane, the low density lipoprotein receptor-related protein 6 (LRP6) coreceptor, as key molecules in neurotransmission modulation and suggest cross-talk between canonical and Wnt/Ca(2+) signaling in central neurons. 

Retracted: No

PubPeer comments:
 In this review published in 2003, table 2 mainly gives percentage. Since it is important to know the population on which the study has been done and the exact number of positive cases and total cases, I extracted the raw data from the paper published by Authier et al. (Arthritis and Rheumatism 2003). ![file] ![file] I think that it s important for comparison and interpretation. , 
 Other items comme from Gherardi et al. (Brain 2001). Here are the items from this source ![file] It is surprising to pool data coming from different sources and potentially different patients. a comment from the authors will be appreciated. , 
 In table 2 page 703: Concurrent autoimmune disease (%): 19 - MS: 9.3 - Hashimoto s thyroiditis: 2.7 - dermatomyositis, polymyositis, inclusion body myositis, rheumatoid arthritis, Sju00f6gren syndrome : 6.7 The authors don t specify the population in which these percentages are established. They should precise. In the text page 705:  In addition to chronique myalgias and fatigue, 15% to 20% of patients with MMF develop a concurrent autoimmune disease ...  Why this difference between 19% in the table and 15% to 20% in the text? The authors should give informations about the studies that allow them to establish such a percentage. , 
 If you cross macrophagic myofasciitis and inclusion body myositis in PubMed, there is only one publication of cases: Cherin P et al. Neuromuscul Dis 2001;11:452-457. This publication reports three cases: - one case (a male patient 34 years old) in which MMF was diagnosed 5 months after last vaccination. This is not true MMF according to the criteria of Gherardi and Authier. - one case (female patient 54 years old) in which MMF was diagnosed 2 years after last vaccination. - one case (male patient 69 years old) in which MMF was diagnosed 5 years after last vaccination. In summary there are only two cases in the world literature demonstrating an association of macrophagic myofasciitis and inclusion body myositis. For me, this is highly evocative of a chance association. , 
 The so-called association of Sju00f6gren syndrome and macrophagic myofasciitis is even rarer. I only found a unique case published by Guis et al. (Arthritis Rheumatol 2002;46:2535-2537). This is case 5 of their publication. However, two of the authors (Sandrine Guis and Jean Roudier) reported that this female patient suffered from rheumatoid arthritis and not Sju00f6gren syndrome in a comment published two years later (Joint Bone Spine 2004;71:164-165). I can t discuss more this nosological problem without examining the patient. Anyway, it means that such an association is far from being classically observed and could be a coincidence. , 
 The so-called association of macrophagic myofasciitis (MMF) and Hashimoto s thyroiditis is also used by these authors to reinforce the autoimmune hypothesis in the case of ASIA syndrome. I don t know the total number of patients with such a thyroid disease and MMF. One case was published in the original publication (Gherardi et al. Lancet 1998). One case was also published by Cherin and Gherardi (Curr Rheum Rep 2000). But I think that this is the same patient. Indeed, Lancet paper concerned the first 14 patients affected by MMF and Cherin and Gherardi paper described the 22 first patients. It is important to review this problem. How many patients present such an association? If there is only one case, this is coincidence. , 
 #3  Concurrent autoimmune disease (%): 19 MS: 9.3 Hashimoto s thyroiditis: 2.7 dermatomyositis, polymyositis, inclusion body myositis, rheumatoid arthritis, Sju00f6gren syndrome : 6.7 The authors don t specify the population in which these percentages are established. They should precise. 9.3 + 2.7 + 6.7 = 18.7%, not 19%. I am confused. , 
 #3 I don t understand the origin of the percentage of patients presenting both multiple sclerosis and macrophagic myofasciitis. In the table published in this paper, this percentage is estimated at 9.3%. In the different series proposed by Gherardi and his group: ![file] How this percentage has been calculated? What is the population that has been used for such a calculation? , 
 #3  In table 2 page 703: Concurrent autoimmune disease (%): 19 MS: 9.3 Hashimoto s thyroiditis: 2.7 dermatomyositis, polymyositis, inclusion body myositis, rheumatoid arthritis, Sju00f6gren syndrome : 6.7 The smallest number of cases compatible with these percentages is 75, I think (2 75 = 2.667%, 5 75 = 6.667%, 7 75 = 9.333%, 14 75 = 18.667%). , 
 - Thank you Hoya Camphorifolia #9. Your proposition is probably the right one. Indeed, the informations of table 2 came from different sources (see my comments #1 #2). Some are established on 30 patients others on 50 patients. Furthermore, the authors wrote:  In France, the total number of recorded cases exceeded 250, including 110 from the authors university hospital, by May 2003. (page 699). So, percentages correspondance is ![file] - The second point concerns multiple sclerosis. Page 705:  In addition to chronic myalgias and fatigue, 15% to 20% of patients with MMF develop a concurrent autoimmune disease, such as multiple sclerosis (MS)-like disease [12, 25]... Reference 12: DA Simpson. Systemic histiocytosis presenting as macrophagic myofasciitis. J Clin Neuromuscul Dis 2002;4:19-22. This is a case report and the author wrote:  Despite this striking MRI, she has no clinical evidence of central nervous system involvement.  Her disorder appears rather to represent a systemic histiocytosis of unknown origin. (page 22). For David A Simpson, this case report is not a case of multiple sclerosis. Why did Gherardi and Authier conclude to MS? At last, there is only one publication associating MS and MMF (Authier et al. Brain 2001; i.e. reference 25). In 2019, the link between these tow disorders seem to be fortuitous. ,