tag:blogger.com,1999:blog-655962722302095847.post2937704515478840437..comments2024-03-29T10:24:53.156+01:00Comments on Epiphany: Treating KCC2 Down-Regulation in Autism, Rett/Down Syndromes, Epilepsy and Neuronal Trauma ?Peter Lloyd-Thomashttp://www.blogger.com/profile/10173383229834614994noreply@blogger.comBlogger8125tag:blogger.com,1999:blog-655962722302095847.post-7632099207095118142018-07-25T20:40:02.164+02:002018-07-25T20:40:02.164+02:00Thought this was interesting and shows there maybe...Thought this was interesting and shows there maybe multiple approaches to KCC2 activation/upregulation:<br /><br />Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2<br /><br />http://www.pnas.org/content/110/1/348<br /><br />5ht2a activation is obviously caused by hallucogenics such as LSD and psilocybin, but also by agmatine. MDMA also activates 5ht2a.Aspie1983https://www.blogger.com/profile/14186355234793738967noreply@blogger.comtag:blogger.com,1999:blog-655962722302095847.post-7830571642273998502017-05-20T23:47:59.098+02:002017-05-20T23:47:59.098+02:00You should read this on MET gene mutation and its ...You should read this on MET gene mutation and its impact on tyrosine kinase efficacy: https://passionlessdrone.wordpress.com/2011/02/25/autism-alphabet-soup-met-hgf-plaur-serpine/<br /><br />Quite fascinatingEmhttps://www.blogger.com/profile/02924636442485818957noreply@blogger.comtag:blogger.com,1999:blog-655962722302095847.post-52023361325866785912016-06-21T07:42:26.708+02:002016-06-21T07:42:26.708+02:00Well, with respect to drugs I am not sure about go...Well, with respect to drugs I am not sure about good ways to lower BDNF, especially since it causes different effects in different cells in the brain, sometimes even the opposite. What BDNF does in the hippocampus is different than what BDNF does in the cerebellum as well as the prefrontal cortex, and that is just discussing neurons (and there are so many types too).<br /><br />Nevertheless, I have read a lot about this with respect to something else I have been working on and I will say that BDNF seems to be activated via excitatory receptors and I know that various patterns of stimulation with rTMS (transcranial magnetic stimulation) are believed to effect excitatory or inhibitory receptors differently. A pattern of stimulation called iTBS is thought to downregulate GABA receptors (increasing LTP [long term potentiation] excitation which is important for learning), while a separate pattern of stimulation called cTBS is thought to wear out or disrupt excitatory receptors (NMDA specifically) causing inhibition or LTD (long term depression) like effects.<br /><br />There is also a protocol I have been very intrigued by lately in a recent paper that involved 6000 pulses at 20hz which is a lot. With interstimulus intervals it takes an hour. What this protocol has been shown to do is increase the cortical silent period (CSP) which is thought to be a measure of true inhibition via GABAb receptors in the central nervous system (the other protocols merely increase transient excitation or depression). It would take a long time to explain this all, but the point is if you block chronically block excitatory receptors or else wear them out (as is thought to happen in clinical depression from overuse), you will decrease BDNF indirectly.<br /><br />So for example in rTMS protocols for depression (the disease), they use high frequency stimulation protocols in the hope of upregulating BDNF, whereas in many rTMS autism studies they have pretty much all used low frequency stimulation (increases LTD) or else cTBS (which is similar). The stuff I have been working on is in this realm but may be far superior to what you can do with rTMS and other forms of artificial stimulation because it can target almost all areas of the brain (even the deep subcortical areas such as the basal ganglia and thalamus) and done so non-invasively. Tylernoreply@blogger.comtag:blogger.com,1999:blog-655962722302095847.post-24861871216578647012016-06-20T16:47:08.109+02:002016-06-20T16:47:08.109+02:00Joel, I do not claim to be an expert. All these p...Joel, I do not claim to be an expert. All these pathways have multiple mechanisms involved and so you cannot really predict the result. Once you have the result, it is easy to explain it. If you have autism and low IGF-1 you have more scope to use IGF-1 as a therapy. However using IGF-1 and GH is known to produce growth effects in the body and there is no way to know what these will be and you may not find out what they were for 10-20 years. People used GH to keep weight low and have good muscle tone, 20 years on they need new hip and knee joints.<br /><br />I think intranasal insulin is very much safer and should give the same potential benefits.Peter Lloyd-Thomashttps://www.blogger.com/profile/10173383229834614994noreply@blogger.comtag:blogger.com,1999:blog-655962722302095847.post-48525731799891432122016-06-20T16:37:53.236+02:002016-06-20T16:37:53.236+02:00Petra, high BDNF may just be a characteristic of s...Petra, high BDNF may just be a characteristic of someone's autism. In this graphic<br /><br />http://www.frontiersin.org/files/Articles/154178/fnins-09-00313-HTML/image_m/fnins-09-00313-g001.jpg<br /><br />autism was split into two groups; either hyper or hypo active pro growth signalling pathways.<br /><br />So if you have high BDNF it may not just be a case of how to lower it. If you have very low BDNF of NGF, it might indeed be wise to change its status, because it may be damaging.<br /><br />There are commercial blood tests to measure BDNF, but apparently they do give quite varying results. Should be good enough to see if you are very high or very low.<br /><br />Low BDNF can be improved by exercise and a good diet.<br /><br />If you have autism and high BDNF, you probably also have high IGF-1 as well. <br /><br />My conclusion was that there is no clever way to down-regulate BDNF, that is why I looked at insulin as a different way to upregulate KCC2.Peter Lloyd-Thomashttps://www.blogger.com/profile/10173383229834614994noreply@blogger.comtag:blogger.com,1999:blog-655962722302095847.post-54872702071676291882016-06-20T15:28:45.552+02:002016-06-20T15:28:45.552+02:00Peter, you say that high levels of BDNF is a major...Peter, you say that high levels of BDNF is a major problem in some autism because this has been linked to epilepsy and as I read, in some OCD and PTSD.<br />Decreased BDNF is also a problem connected with many serious central nervous system disorders, since it is needed for survival and protection.<br />How can you measure BDNF to see if you need to upregulate or downregulate? I suppose it's an important biomarker of someone's condition and treatment.<br />Do you think flavonoids can have an impact on BDNF? If so in what way?<br />Anonymoushttps://www.blogger.com/profile/16138974464162606874noreply@blogger.comtag:blogger.com,1999:blog-655962722302095847.post-44383392721044633562016-06-20T13:14:23.297+02:002016-06-20T13:14:23.297+02:00I have question for you, Peter, and perhaps Tyler ...I have question for you, Peter, and perhaps Tyler can chime in: what's your understanding of IGF-1 administration and mtor? The little information I've been able to gather is difficult to interpret. I have low IGF-1, but have yet to try to raise it. However, I'm wary that increased IGF-1 would also lead to mtor increase, and that may not be a problem in Rett's, but most likely in most other forms of autism. I don't believe Buxbaum et al's study on increlex for idiopathic autism has been published yet. Best, JoelAnonymousnoreply@blogger.comtag:blogger.com,1999:blog-655962722302095847.post-69524925894711879142016-06-19T06:42:33.171+02:002016-06-19T06:42:33.171+02:00With respect to insulin signaling and the very gia...With respect to insulin signaling and the very giant elephant in the room nobody wants to discuss with respect to autism, a paper that more or less beats a dead horse came out in the last couple days which suggests that poor maternal line nutrition can negatively impact mitochrondia for up to 3 generations (at least in mice):<br /><br />http://www.cell.com/cell-reports/pdf/S2211-1247(16)30663-5.pdf<br /><br />Every time these obesity and poor lifestyle issues are critically brought up on discussion boards I have read, the first reply is "so you are gonna blame it all on the mom now". What this shows is that your great grandma could of been eating cookies and bacon like crazy and you could have genetically dysfunctional mitochondria because of her past behavior. The effect of course is stronger when it comes to the grandmother and mother, but this likely explains why women around the world, and especially in the United States where 70% of women are overweight, over 40% of women are classified as obese, and 10% are classified as morbidly obese. Dysfunctional mitochondria lead to all kinds of problems and of course might as well be considered a standard symptom of autism, but it also seems to lead to more obesity.<br /><br />Part of the rise in autism is obviously due to increased diagnosis and maybe even overdiagnosis, but the single biggest correlation with autism in the last 30 years and its rise is poor maternal health and the obesity that ensues.<br /><br />But even if you do everything right as a soon to be mother and don't happen to be obese, the sins of your own mother can negatively impact the mitochrondial health of any children you may have (that is if you don't get metabolic syndrome and PCOS, and are therefore unable to conceive a child).<br /><br />Nevertheless, prevention at this point won't help my children, but perhaps high levels of IGF-1 in those with autism is a reaction to decreased or diseased receptors, including the ones responsible for helping to regulate KCC2. Maybe this is one of many other reasons why ketogenic diets help some with autism and many with epilepsy as they restrict insulin levels in the body, thereby allowing the receptors that bind to insulin to upregulate over time as a homeostatic response. Maybe what is needed is a drug that binds to the appropriate receptor (while ignoring the corresponding autoreceptors) to normalize GABAergic plasticity, and also does not effect the rest of the body.<br /><br />Maybe trehalose would be a start as among many things it does, it upregulates insulin receptors:<br /><br />http://www.ncbi.nlm.nih.gov/pubmed/24418873Tylernoreply@blogger.com