Miswiring the brain: Δ9‐tetrahydrocannabinol disrupts cortical development

[Happy 7]

Miswiring the brain: Δ9‐tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin‐2 degradation pathway


Giuseppe Tortoriello, Claudia V Morris, Alan Alpar, Janos Fuzik, Sally L Shirran, Daniela Calvigioni, Erik Keimpema, Catherine H Botting, Kirstin Reinecke, Thomas Herdegen, Michael Courtney, Yasmin L Hurd, Tibor Harkany


DOI: 10.1002/embj.201386035 |Published 27.01.2014


Children exposed in utero to cannabis present permanent neurobehavioral and cognitive impairments. Psychoactive constituents from Cannabis spp., particularly Δ9‐tetrahydrocannabinol (THC), bind to cannabinoid receptors in the fetal brain. However, it is unknown whether THC can trigger a cannabinoid receptor‐driven molecular cascade to disrupt neuronal specification. Here, we show that repeated THC exposure disrupts endocannabinoid signaling, particularly the temporal dynamics of CB1 cannabinoid receptor, to rewire the fetal cortical circuitry. By interrogating the THC‐sensitive neuronal proteome we identify Superior Cervical Ganglion 10 (SCG10)/stathmin‐2, a microtubule‐binding protein in axons, as a substrate of altered neuronal connectivity. We find SCG10 mRNA and protein reduced in the hippocampus of midgestational human cannabis‐exposed fetuses, defining SCG10 as the first cannabis‐driven molecular effector in the developing cerebrum. CB1 cannabinoid receptor activation recruits c‐Jun N‐terminal kinases to phosphorylate SCG10, promoting its rapid degradation in situ in motile axons and microtubule stabilization. Thus, THC enables ectopic formation of filopodia and alters axon morphology. These data highlight the maintenance of cytoskeletal dynamics as a molecular target for cannabis, whose imbalance can limit the computational power of neuronal circuitries in affected offspring.

 

[Piel]

A new FAS? Pregnant women need to stay clean in order for the foetus to develop "normally". I don´t mean to be a chauvinist, I just believe that every child should be given the right to normal in utero development. Non-pregnant women are free to LL

 

[TheCleanGame]

My child is quite intelligent and has no issues showing in the first several years now. Wouldn't be here if it weren't for cannabis.

Anyone have the full paper? The link doesn't provide any details on how their "Unbiased" study was conducted. Most likely a 100% pure THC study with animals, extrapolated to humans again.

Keep it Clean!

 

[Storm Shadow]

Blah Blah Blah

All Countries associated with these studies stand to lose so much money to the legalization of Marijuana.... let the BS just continue to roll...

I have family members in Iran in their 90's doing typical daily farm work and aren't even close to slowing down... here is the kicker....they smoke hash 24-7!!!!!!!!!!

 

[candidly]

"These data highlight the maintenance of cytoskeletal dynamics as a molecular target for cannabis, whose imbalance can limit the computational power of neuronal circuitries in affected offspring."

What the fuck does that even MEAN?

How does one measure the "computational power of neuronal circuitries"?

Haven't even read the paper, and I can already tell this is likely a bullshit study.

I'm better than most folks at parsing and understanding scientific jargon....but this abstract is damn near unreadable. What are they even trying to say? It's so loaded with buzzwords, like they're trying to baffle you with bullshit.

I don't know for a fact, but I strongly suspect that cannabis exposure doesn't do a damn thing to hurt a fetus.

"The authors declare they have no conflict of interest."

Well, that settles it then!

 

[StayHigh149]

I didn't understand much of the mumbo jumbo in that article.

I would agree tho that pregnant women probably should not partake in cannabis while pregnant, just like alcohol or harder drugs. I don't base that opinion in science tho, just thru my "conditioned thoughts". It may actually not b harmful at all...what do I know

 

[Piel]

I didn't understand much of the mumbo jumbo in that article.

I would agree tho that pregnant women probably should not partake in cannabis while pregnant, just like alcohol or harder drugs. I don't base that opinion in science tho, just thru my "conditioned thoughts". It may actually not b harmful at all...what do I know

My thoughts exactly.

 

[GSPfan]

This study looks like bs. Mary Jane can be a wonderful help with morning sickness. But everything in moderation. Its not good to abuse anything especially while prego.

 

[dddaver]

"The authors declare they have no conflict of interest." means nothing to me.
INMHO, it just means just if they were anti at the start, they still would be irregardless what anyone said. Even them having said that makes me suspicious. And REAL studies don't use so much mumbo jumbo, only in studies intended to be peer reviewed, because the intent is to be understood. I call BS. Big BS.

 

[Skip]

Thus, THC enables ectopic formation of filopodia and alters axon morphology. These data highlight the maintenance of cytoskeletal dynamics as a molecular target for cannabis, whose imbalance can limit the computational power of neuronal circuitries in affected offspring.

Yes, this is a bunch of mumbo jumbo.

"computational power of neuronal circuitries".

What they're trying to do is tag something negative on their results which showed an effect, but not necessarily a NEGATIVE effect. So they tried to make it look like what is going on in the fetus to be dangerous by clouding their results with a negative "possibility" which they refused to put in layman's terms because such an effect is made up!

They noted lower birth weight among babies who tested positive for THC. Well a recent study found that despite what everyone expects, marijuana users have a LOWER average weight than non users. So perhaps marijuana is preventing the baby from being overweight (like other mothers who probably have poor diets). Mother's poor diets are probably more of a problem for newborns than THC.

I don't doubt there's an effect upon the fetus, just as alcohol, tobacco and other drugs can effect a growing fetus, they don't compare the results to any of these other substances so how do we know the effects in relative terms?

And we all know personally how cannabis effects our short-term memory, which may be more critical in a developing fetus.

So bottom line is pregnant mothers should try to avoid using cannabis on a regular basis while pregnant. However if needed it could be of medical benefit to both mother and baby. More research is obviously needed.

Unfortunately most research in the US must be approved by the Gov't which usually only approves such research if it is looking for NEGATIVE effects of cannabis. This has been true for decades.

 

[mr.shiva]

I don't buy that research. My 4 yo reads, writes, tells knock knock jokes, counts to 100, obiviously has a great memory.

 

[Jhhnn]

Standard right wing propaganda technique, splashy headlines creating public opinion ahead of the facts using vague references to supposedly "scientific" work. Once that opinion is established, facts have little effect upon it. When the study is discredited, it's still the first liar's words that hold the greatest weight, particularly if he was telling people what they wanted to hear.

The same principle is applied to interpretation of events as well, with examples too numerous to mention.

 

[justpassnthru]

The proof is in the pudding.

I knew a pothead gal that is a multi-daily toker. Her 40 year old son is a pharmacist. The only real difference in him is (and Ed Rosenthal will say the same thing); "none of my children use cannabis." Probably, imho..their endocannabinoid system is fed properly, in utero.

The entire abstract including disclaimers and opinions would be a bit more interesting from the first post? jpt

 

[TanzanianMagic]

Miswiring the brain: Δ9‐tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin‐2 degradation pathway


We find SCG10 mRNA and protein reduced in the hippocampus of midgestational human cannabis‐exposed fetuses, defining SCG10 as the first cannabis‐driven molecular effector in the developing cerebrum. CB1 cannabinoid receptor activation recruits c‐Jun N‐terminal kinases to phosphorylate SCG10, promoting its rapid degradation in situ in motile axons and microtubule stabilization. Thus, THC enables ectopic formation of filopodia and alters axon morphology. These data highlight the maintenance of cytoskeletal dynamics as a molecular target for cannabis, whose imbalance can limit the computational power of neuronal circuitries in affected offspring.

What was the sample size? Were there other factors that could create the same effect?

 

[madscientist81]

Just want to say to all those saying they are using too much jargon, mumbo jumbo, bs etc etc. This is in fact what many abstracts in molecular biology/neuroscience read like. It just seems like bs because this wasn't intended for a lay audience, which many of you are. That being said, I agree that studies are funded more to find negative effects of cannabis use than the other way around. Like many others have said, I'm of the opinion that it is preferable to minimize exposing developing humans to as much stuff as possible. I have no doubt that cannabis can effect the developing brain (though not as badly as most other things). Considering that cannabinoid receptors are among the most abundant receptors in the human brain, that system is even more crucial. The main issue is feedback in biology- give opiates and the brain adapts by reducing it's opiate receptors and production of endorphins etc. Same thing in that giving THC to developing brain could effect the endocannabinoid system. Of course it is difficult to separate such things if you have a parent(s) that has a pre-existing dysfunction in their endocannabinoid system who uses cannabis to self medicate etc. They use when pregnant. So does anything wrong with the child indicate the THC disrupted their endocannabinoid development, or was it something they inherited from their parents? Lastly as already mentioned, moderation is usually the key. As long as used in moderation, no big deal. I'd say better to focus people on better nutrition during pregnancy etc vs big deal over pot.

 

[photoperiodic]

I have known a lot of women whole use while pregnant. not a single issue the children are all healthy generally healthier than the average population. propaganda meant to defile the honest truth women who use pass on genetic benefits not yet understood

 

[trichrider]

Miswiring the brain: Δ9‐tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin‐2 degradation pathway


Giuseppe Tortoriello, Claudia V Morris, Alan Alpar, Janos Fuzik, Sally L Shirran, Daniela Calvigioni, Erik Keimpema, Catherine H Botting, Kirstin Reinecke, Thomas Herdegen, Michael Courtney, Yasmin L Hurd, Tibor Harkany


DOI: 10.1002/embj.201386035 |Published 27.01.2014


Children exposed in utero to cannabis present permanent neurobehavioral and cognitive impairments. Psychoactive constituents from Cannabis spp., particularly Δ9‐tetrahydrocannabinol (THC), bind to cannabinoid receptors in the fetal brain. However, it is unknown whether THC can trigger a cannabinoid receptor‐driven molecular cascade to disrupt neuronal specification. Here, we show that repeated THC exposure disrupts endocannabinoid signaling, particularly the temporal dynamics of CB1 cannabinoid receptor, to rewire the fetal cortical circuitry. By interrogating the THC‐sensitive neuronal proteome we identify Superior Cervical Ganglion 10 (SCG10)/stathmin‐2, a microtubule‐binding protein in axons, as a substrate of altered neuronal connectivity. We find SCG10 mRNA and protein reduced in the hippocampus of midgestational human cannabis‐exposed fetuses, defining SCG10 as the first cannabis‐driven molecular effector in the developing cerebrum. CB1 cannabinoid receptor activation recruits c‐Jun N‐terminal kinases to phosphorylate SCG10, promoting its rapid degradation in situ in motile axons and microtubule stabilization. Thus, THC enables ectopic formation of filopodia and alters axon morphology. These data highlight the maintenance of cytoskeletal dynamics as a molecular target for cannabis, whose imbalance can limit the computational power of neuronal circuitries in affected offspring.

impossible to test. there is no human testing being done. it had to be rats or dogs and they make it look as if it was conducted on humans.
...explain how they measured computational power of neuronal circuitries of newborns...last sentence says: it makes kids stupid...right.
nothing about neurogenesis...





Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects
Wen Jiang,1,2 Yun Zhang,1 Lan Xiao,1 Jamie Van Cleemput,1 Shao-Ping Ji,1 Guang Bai,3 and Xia Zhang1

1Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. 2Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China. 3Department of Biomedical Sciences, Dental School, Program in Neuroscience, University of Maryland, Baltimore, Maryland, USA.
Address correspondence to: Xia Zhang, Neuropsychiatry Research Unit, 103 Wiggins Road, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E4. Phone: (306) 966-2288; Fax: (306) 966-8830; E-mail: zhangxia@duke.usask.ca .

Author information ► Article notes ► Copyright and License information ►
Received April 29, 2005; Accepted August 9, 2005.

Copyright © 2005, American Society for Clinical Investigation


This article has been cited by other articles in PMC.




Go to:
Abstract

The hippocampal dentate gyrus in the adult mammalian brain contains neural stem/progenitor cells (NS/PCs) capable of generating new neurons, i.e., neurogenesis. Most drugs of abuse examined to date decrease adult hippocampal neurogenesis, but the effects of cannabis (marijuana or cannabinoids) on hippocampal neurogenesis remain unknown. This study aimed at investigating the potential regulatory capacity of the potent synthetic cannabinoid HU210 on hippocampal neurogenesis and its possible correlation with behavioral change. We show that both embryonic and adult rat hippocampal NS/PCs are immunoreactive for CB1 cannabinoid receptors, indicating that cannabinoids could act on CB1 receptors to regulate neurogenesis. This hypothesis is supported by further findings that HU210 promotes proliferation, but not differentiation, of cultured embryonic hippocampal NS/PCs likely via a sequential activation of CB1 receptors, Gi/o proteins, and ERK signaling. Chronic, but not acute, HU210 treatment promoted neurogenesis in the hippocampal dentate gyrus of adult rats and exerted anxiolytic- and antidepressant-like effects. X-irradiation of the hippocampus blocked both the neurogenic and behavioral effects of chronic HU210 treatment, suggesting that chronic HU210 treatment produces anxiolytic- and antidepressant-like effects likely via promotion of hippocampal neurogenesis.


Go to:
Introduction

Cannabis (marijuana, hashish, or cannabinoids) has been used for medical and recreational purposes for many centuries and is likely the only medicine or illicit drug that has constantly evoked tremendous interest or controversy within both the public domain and medical research. Cannabinoids appear to be able to modulate pain, nausea, vomiting, epilepsy, ischemic stroke, cerebral trauma, multiple sclerosis, tumors, and other disorders in humans and/or animals (1–7). However, marijuana has been the most commonly used illicit drug in developed countries, producing acute memory impairment and dependence/withdrawal symptoms in chronic users and animal models (6, 8–10). Cannabis acts on 2 types of cannabinoid receptors, the CB1 and CB2 receptors, which are distributed mainly in the brain and immune system, respectively. In the brain, CB1 receptors are also targeted by endogenous cannabinoids (i.e., endocannabinoids) such as anandamide (AEA), 2-arachidonylglycerol, and arachidonylethanolamide (1, 6, 10, 11).
The recent discovery that the hippocampus is able to generate new neurons (i.e., neurogenesis) throughout the lifespan of mammals, including humans, has changed the way we think about the mechanisms of psychiatric disorders (12) and drug addiction (13). The subgranular zone of the dentate gyrus (SGZ) in the adult brain contains neural stem/progenitor cells (NS/PCs) capable of producing thousands of new granule cells per day (14). We, and others, have shown that these newborn hippocampal neurons are functionally integrated into the existing neuroanatomical circuitry (15, 16) and are positively correlated with hippocampus-dependent learning and memory processes (17) and the developmental mechanisms of stress and mood disorders (12). Recent studies have further shown that chronic fluoxetine treatment produced antidepressant and anxiolytic effects (18, 19) and the anxiolytic effects are likely achieved by promoting hippocampal neurogenesis (18).
Chronic administration of the major drugs of abuse including opiates, alcohol, nicotine, and cocaine has been reported to suppress hippocampal neurogenesis in adult rats (20–23), suggesting a potential role of hippocampal neurogenesis in the initiation, maintenance, and treatment of drug addiction (13). The recent finding of prominently decreased hippocampal neurogenesis in CB1-knockout mice (24) suggests that CB1 receptor activation by endogenous, plant-derived, or synthetic cannabinoids may promote hippocampal neurogenesis. However, endogenous cannabinoids have been reported to inhibit adult hippocampal neurogenesis (25). Nevertheless, it is possible that exo- and endocannabinoids could differentially regulate hippocampal neurogenesis, as exo- and endocannabinoids act as full or partial agonists on CB1 receptors, respectively (11).
The goal of the present study was to test the hypothesis that the potent synthetic cannabinoid HU210 is able to promote hippocampal neurogenesis, leading to the anxiolytic and antidepressant effects of cannabinoids. We demonstrate here that both HU210 and the endocannabinoid AEA promote proliferation of embryonic hippocampal NS/PCs without significant effects on their differentiation, resulting in more newborn neurons. The effects of HU210 on adult hippocampal neurogenesis were quantified in freely moving rats and were correlated with behavioral testing. We show that 1 month after chronic HU210 treatment, rats display increased newborn neurons in the hippocampal dentate gyrus and significantly reduced measures of anxiety- and depression-like behavior. Thus, cannabinoids appear to be the only illicit drug whose capacity to produce increased hippocampal newborn neurons is positively correlated with its anxiolytic- and antidepressant-like effects.


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1253627/

Cannabinoids promote embryonic and adult hippocampus neurogenesis
and produce anxiolytic- and antidepressant-like effects
by
Jiang W, Zhang Y, Xiao L, Van Cleemput J, Ji SP, Bai G, Zhang X.
Neuropsychiatry Research Unit, Department of Psychiatry,
University of Saskatchewan,
Saskatoon, Saskatchewan, Canada.
J Clin Invest. 2005 Oct 13

ABSTRACT

The hippocampal dentate gyrus in the adult mammalian brain contains neural stem/progenitor cells (NS/PCs) capable of generating new neurons, i.e., neurogenesis. Most drugs of abuse examined to date decrease adult hippocampal neurogenesis, but the effects of cannabis (marijuana or cannabinoids) on hippocampal neurogenesis remain unknown. This study aimed at investigating the potential regulatory capacity of the potent synthetic cannabinoid HU210 on hippocampal neurogenesis and its possible correlation with behavioral change. We show that both embryonic and adult rat hippocampal NS/PCs are immunoreactive for CB1 cannabinoid receptors, indicating that cannabinoids could act on CB1 receptors to regulate neurogenesis. This hypothesis is supported by further findings that HU210 promotes proliferation, but not differentiation, of cultured embryonic hippocampal NS/PCs likely via a sequential activation of CB1 receptors, G(i/o) proteins, and ERK signaling. Chronic, but not acute, HU210 treatment promoted neurogenesis in the hippocampal dentate gyrus of adult rats and exerted anxiolytic- and antidepressant-like effects. X-irradiation of the hippocampus blocked both the neurogenic and behavioral effects of chronic HU210 treatment, suggesting that chronic HU210 treatment produces anxiolytic- and antidepressant-like effects likely via promotion of hippocampal neurogenesis.

http://www.biopsychiatry.com/cannabinoids-neogenesis.htm

Cannabinoids boost neurogenesis?

New study suggests the chemicals may also act as anxiolytics and antidepressants.
By Graciela Flores(graciela_flores@nasw.org) | October 14, 2005

Cannabinoids promote neurogenesis in embryonic and adult rats, and produce anxiolytic- and antidepressant-like effects, according to a new report in the current issue of The Journal of Clinical Investigation. The effects appear to contradict those seen from other studied drugs of abuse, the authors note.
"Most drugs of abuse such as nicotine, heroine, and cocaine suppress neurogenesis in these cells, but the effects of cannabinoids weren't clear. We show that cannabinoids, in fact, promote neurogenesis," study author Xia Zhang of the University of Saskatchewan in Saskatoon, Canada, told The Scientist.
During the study, Zhang and his colleagues analyzed the effect of the synthetic cannabinoid HU210, an agonist of the cannabinoid receptor CB1, on neural progenitor cells in the hippocampal dentate gyrus. They found that HU210 increased cell proliferation in vitro, and did so in vivo after chronic treatment. Antidepressants produce a similar pattern of cell proliferation, inspiring the authors to examine the influence of HU210 on behavior, explained Ronald Duman of Yale University School of Medicine in an Email.

http://www.the-scientist.com/?articles.view/articleNo/23471/title/Cannabinoids-boost-neurogenesis-/


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