Depressed Mice Reveal Critical Chemical Pathway for Treatment

Depressed Mice Reveal Critical Chemical Pathway for Treatment

Joined: April 1st, 2004, 4:56 pm

February 5th, 2008, 11:52 am #1

Depressed Mice Reveal Critical Chemical Pathway for Treatment
 

http://www.webwire.com/ViewPressRel.asp?aId=58216

<DIV>WEBWIRE – Friday, February 01, 2008</DIV>
DURHAM, N.C. – Blocking production of a single enzyme alleviates symptoms of depression and anxiety in mice that have low serotonin levels, Duke <A class=iAs style="FONT-WEIGHT: normal; FONT-SIZE: 100%; PADDING-BOTTOM: 1px; COLOR: darkgreen; BORDER-BOTTOM: darkgreen 0.07em solid; BACKGROUND-COLOR: transparent; TEXT-DECORATION: underline" href="http://www.webwire.com/ViewPressRel.asp?aId=58216#" target=_blank itxtdid="5319558">University</A> Medical Center researchers have found.



Serotonin, a chemical that helps brain cells communicate with one another, is the target of the most successful anti-depressant medications. Low levels of serotonin are implicated in depression and many other psychiatric disorders, including increased anxiety, aggression and obsessive-compulsive disorder.



The Duke team created mice with a mutation in the gene for tryptophan hydroxylase 2 (Tph2), which helps make serotonin in the brain. An equivalent human mutation has been identified in some people with unipolar major depression. These patients often show resistance to treatment with SSRI antidepressant drugs.



Mice with the mutation had 80 percent less serotonin in their brains than normal mice and exhibited behavioral changes that mirror the symptoms of humans with low serotonin.



However, the study revealed a possible means for alleviating these symptoms. The drop in serotonin levels was accompanied by an increase in the activity of another enzyme, called glycogen synthase kinase 3 (GSK-3), which helps a cell respond to chemical signals, including serotonin.



Communication between cells operates much like a string of medieval signaling towers – a fire lighted in one tower alerts the next in the chain, quickly transmitting a message across far distances. The Duke researchers discovered that blocking one of these signaling towers, GSK-3, restored normal behavior in the mutant mice.



The findings appear in the January 29, 2008 edition of the Proceedings of the National Academy of Sciences. The study was funded by the National Institutes of Health, the Lennon Family Foundation, NARSAD and the Canadian Institutes of Health Research.



GSK-3 is well known in the pharmaceutical industry – many different psychiatric drugs block the enzyme, including lithium, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs).



The researchers tested the SSRI drug fluoxetine (Prozac) in the mutant mice, finding that short-term treatment relieved the animal’s depressive symptoms and inhibited GSK-3 activity in the brain. The team is now evaluating the effects of long-term treatment with SSRI drugs.



They also prevented depression from developing by breeding mice with a mutation in the gene for GSK-3. "That GSK-3 is involved was expected. But the fact that removing one version of the GSK-3B gene reversed the behavior was quite surprising to us" said lead author Jean-Martin Beaulieu, Ph.D., now at Université Laval in Quebec. "This suggests that serotonin’s effects on mood and aggression may be partly controlled through regulation of GSK-3 activity"



The dramatic drop in serotonin seen in the mice is caused by a single-letter difference in the spelling of a gene that has 200,000 letters of DNA code. This one-letter change is called a single nucleotide polymorphism, or SNP – a site where the DNA sequence of individuals differs by just one of four nucleotides (A, T, C or G). For example, some people may have G at a particular site, while others have an A. The SNP studied by the Duke researchers affects the Tph2 gene, built of some 100,000 nucleotide pairs.



The study also confirms that the Tph2 enzyme is critical for making brain serotonin, said Xiaodong Zhang, Ph.D., study co-author and an assistant professor at the Duke-NUS Graduate Medical <A class=iAs style="FONT-WEIGHT: normal; FONT-SIZE: 100%; PADDING-BOTTOM: 1px; COLOR: darkgreen; BORDER-BOTTOM: darkgreen 0.07em solid; BACKGROUND-COLOR: transparent; TEXT-DECORATION: underline" href="http://www.webwire.com/ViewPressRel.asp?aId=58216#" target=_blank itxtdid="5319385">School</A> Singapore. The results imply that humans with this mutation may have serious deficits in brain serotonin, he said.



In addition to revealing new clues to serotonin signaling in the brain, the Tph2-mutant mice could also serve as an animal model of drug-resistant depression. The Duke researchers have patented the strain of mice used in the study, said senior study author Marc Caron, Ph.D., James B. Duke professor of cell biology.



"These animals may be one of the better models for preclinical studies" Caron said. "We now have an animal model that mimics many of the things you would expect of people that are depressed"



Collaborators on the study include Ramona Rodriguiz, Tatyana Sotnikova, Michael Cools, William Wetsel and Raul Gainetdinov, all of Duke.
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Joined: April 1st, 2004, 4:56 pm

February 5th, 2008, 11:53 am #2

indeed where could one find a mouse psychiatrist to diagnose said mouse depression
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Joined: April 1st, 2004, 4:56 pm

February 5th, 2008, 11:55 am #3

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<H1 class=abstract-heading>Sonic hedgehog expression in Gli3 depressed mouse embryo, Pdn/Pdn </H1></DIV></DIV>
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<STRONG>Authors: </STRONG>Ueta E.<FONT color=#336699>1</FONT>;&nbsp;Maekawa M.<FONT color=#336699>1</FONT>;&nbsp;Morimoto I.<FONT color=#336699>1</FONT>;&nbsp;Nanba E.<FONT color=#336699>2</FONT>;&nbsp;Naruse I.

<STRONG>Source:</STRONG> <A title="Congenital Anomalies" href="http://www.ingentaconnect.com/content/bsc/cga;jsessionid=612ng89ddb9lh.victoria"><FONT color=#336699>Congenital Anomalies</FONT></A>, Volume 44,&nbsp;Number 1, March 2004 , pp. 27-32(6)

<STRONG>Publisher: </STRONG><A title=publisher href="http://www.ingentaconnect.com/content/bp;jsessionid=612ng89ddb9lh.victoria"><FONT color=#336699>Blackwell Publishing</FONT></A>
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<STRONG>Abstract:</STRONG>


The phenotype of the genetic polydactyly/arhinencephaly mouse (Pdn/Pdn) is similar to Greig cephalopolysyndactyly syndrome (GCPS), which is induced by mutation of GLI3. Suppression of Gli3 gene expression has been observed in Pdn/Pdn. Thus, the gene responsible for Pdn/Pdn has been considered to be Gli3. Recently, the mutation point was demarcated, that is, a transposon was inserted into intron 3 of the Gli3 gene in the Pdn mouse. Forward and reverse primers were constructed in intron 3 near the insertion point. A forward primer in the long terminal repeat region of the transposon was also constructed. Now we can discriminate +/+, Pdn/+, Pdn/Pdn embryos from the PCR products. After genotyping of the Pdn embryos, Gli3 and other correlated gene expressions, such as sonic hedgehog (Shh), Bmp-2, Bmp-4, ptc-1, were analyzed by real-time PCR method. Gli3 gene expression in Pdn/Pdn was suppressed to 20–30% of +/+, and that in Pdn/+ was about 60% of +/+ through all the embryonic and neonatal periods examined. As Shh has been considered to be an antagonist of Gli3, Shh expression was analyzed, and a difference among genotypes was observed only on day 9 of gestation. We could not detect any alterations among genotypes in other gene expressions examined. Gli3 and Shh gene expression were also analyzed on day 9 by whole-mount in situ hybridization in the +/+ and Pdn/Pdn embryos. Neuroectoderm was positive by Gli3 probe in +/+ but not in Pdn/Pdn. Notochord, floor plate and prechordal mesoderm were positive by Shh probe both in +/+ and Pdn/Pdn embryos, but ectopic and/or over-expression of Shh were not observed in Pdn/Pdn embryos. </DIV>
<DIV id=info>
<STRONG>Keywords:</STRONG> <FONT color=#336699>arhinencephaly</FONT>; <FONT color=#336699>Gli3</FONT>; <FONT color=#336699>arhinencephaly</FONT>; <FONT color=#336699>polydactyly</FONT>; <A href="http://www.ingentaconnect.com/search;jsessionid=612ng89ddb9lh.victoria?database=1&title=sonic hedgehog"><FONT color=#336699>sonic hedgehog</FONT></A>

<STRONG>Document Type:</STRONG> Research article

<STRONG>DOI:</STRONG> 10.1111/j.1741-4520.2003.00005.x

<STRONG>Affiliations:</STRONG> <STRONG>1: <A name=aff_1></A></STRONG>School of Health Science, Faculty of Medicine and <A name="aff_ School of Health Science, Faculty of Medicine and&#13;&#10;"></A><STRONG>2: <A name=aff_2></A></STRONG>Division of Functional Genomics, Tottori University, Japan<A name="aff_ Division of Functional Genomics, Tottori University, Japan"></A>
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Joined: April 1st, 2004, 4:56 pm

February 5th, 2008, 11:56 am #4


&nbsp;

http://www.nature.com/mp/journal/v9/n4/ ... 1457a.html

<P id=cite>Molecular Psychiatry (2004) 9, 326–357. doi:10.1038/sj.mp.4001457 Published online 13 January 2004

<H2 id=atl>In search of a depressed mouse: utility of models for studying depression-related behavior in genetically modified mice</H2>
<P id=aug>J F&nbsp;Cryan<A title="affiliated with 1" href="http://www.nature.com/mp/journal/v9/n4/ ... aff1">1</A> and C&nbsp;Mombereau<A title="affiliated with 1" href="http://www.nature.com/mp/journal/v9/n4/ ... aff1">1</A>

<DIV id=affiliations-notes>
<P id=aff><A name=aff1>1</A>Neuroscience Research, The Novartis Institutes for BioMedical Research, Basel, Switzerland

<P class=caff>Correspondence: JF Cryan, PhD, Psychiatry Program, Neuroscience Research, The Novartis Institutes for BioMedical Research, WSJ 386.344, Novartis Pharma AG, Basel CH-4002, Switzerland. E-mail: [url=mailto:john_f.cryan@pharma.novartis.com]john_f.cryan@pharma.novartis.com[/url]

<P class=prdates>Received 23&nbsp;July&nbsp;2003; Revised 15&nbsp;September&nbsp;2003; Accepted 15&nbsp;September&nbsp;2003; Published online 13&nbsp;January&nbsp;2004.
</DIV>
<DIV id=abs><A class=backtotop href="http://www.nature.com/mp/journal/v9/n4/ ... ">Top<SPAN class=hidden> of page</SPAN></A>
Abstract
<P class="abs lead">The ability to modify mice genetically has been one of the major breakthroughs in modern medical science affecting every discipline including psychiatry. It is hoped that the application of such technologies will result in the identification of novel targets for the treatment of diseases such as depression and to gain a better understanding of the molecular pathophysiological mechanisms that are regulated by current clinically effective antidepressant medications. The advent of these tools has resulted in the need to adopt, refine and develop mouse-specific models for analyses of depression-like behavior or behavioral patterns modulated by antidepressants. In this review, we will focus on the utility of current models (eg forced swim test, tail suspension test, olfactory bulbectomy, learned helplessness, chronic mild stress, drug-withdrawal-induced anhedonia) and research strategies aimed at investigating novel targets relevant to depression in the mouse. We will focus on key questions that are considered relevant for examining the utility of such models. Further, we describe other avenues of research that may give clues as to whether indeed a genetically modified animal has alterations relevant to clinical depression. We suggest that it is prudent and most appropriate to use convergent tests that draw on different antidepressant-related endophenotypes, and complimentary physiological analyses in order to provide a program of information concerning whether a given phenotype is functionally relevant to depression-related pathology.

<DIV class=keyw-abbr>
<H4 class=keywords>Keywords: </H4>
<P class=keywords>antidepressant, endophenotype, forced swim test, affective disorder, knockout
</DIV></DIV>
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Joined: April 1st, 2004, 4:56 pm

February 5th, 2008, 11:58 am #5

Depressed Mice Reveal Critical Chemical Pathway for Treatment
&nbsp;

http://www.webwire.com/ViewPressRel.asp?aId=58216

<DIV>WEBWIRE – Friday, February 01, 2008</DIV>
DURHAM, N.C. – Blocking production of a single enzyme alleviates symptoms of depression and anxiety in mice that have low serotonin levels, Duke <A class=iAs style="FONT-WEIGHT: normal; FONT-SIZE: 100%; PADDING-BOTTOM: 1px; COLOR: darkgreen; BORDER-BOTTOM: darkgreen 0.07em solid; BACKGROUND-COLOR: transparent; TEXT-DECORATION: underline" href="http://www.webwire.com/ViewPressRel.asp?aId=58216#" target=_blank itxtdid="5319558">University</A> Medical Center researchers have found.



Serotonin, a chemical that helps brain cells communicate with one another, is the target of the most successful anti-depressant medications. Low levels of serotonin are implicated in depression and many other psychiatric disorders, including increased anxiety, aggression and obsessive-compulsive disorder.



The Duke team created mice with a mutation in the gene for tryptophan hydroxylase 2 (Tph2), which helps make serotonin in the brain. An equivalent human mutation has been identified in some people with unipolar major depression. These patients often show resistance to treatment with SSRI antidepressant drugs.



Mice with the mutation had 80 percent less serotonin in their brains than normal mice and exhibited behavioral changes that mirror the symptoms of humans with low serotonin.



However, the study revealed a possible means for alleviating these symptoms. The drop in serotonin levels was accompanied by an increase in the activity of another enzyme, called glycogen synthase kinase 3 (GSK-3), which helps a cell respond to chemical signals, including serotonin.



Communication between cells operates much like a string of medieval signaling towers – a fire lighted in one tower alerts the next in the chain, quickly transmitting a message across far distances. The Duke researchers discovered that blocking one of these signaling towers, GSK-3, restored normal behavior in the mutant mice.



The findings appear in the January 29, 2008 edition of the Proceedings of the National Academy of Sciences. The study was funded by the National Institutes of Health, the Lennon Family Foundation, NARSAD and the Canadian Institutes of Health Research.



GSK-3 is well known in the pharmaceutical industry – many different psychiatric drugs block the enzyme, including lithium, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs).



The researchers tested the SSRI drug fluoxetine (Prozac) in the mutant mice, finding that short-term treatment relieved the animal’s depressive symptoms and inhibited GSK-3 activity in the brain. The team is now evaluating the effects of long-term treatment with SSRI drugs.



They also prevented depression from developing by breeding mice with a mutation in the gene for GSK-3. "That GSK-3 is involved was expected. But the fact that removing one version of the GSK-3B gene reversed the behavior was quite surprising to us" said lead author Jean-Martin Beaulieu, Ph.D., now at Université Laval in Quebec. "This suggests that serotonin’s effects on mood and aggression may be partly controlled through regulation of GSK-3 activity"



The dramatic drop in serotonin seen in the mice is caused by a single-letter difference in the spelling of a gene that has 200,000 letters of DNA code. This one-letter change is called a single nucleotide polymorphism, or SNP – a site where the DNA sequence of individuals differs by just one of four nucleotides (A, T, C or G). For example, some people may have G at a particular site, while others have an A. The SNP studied by the Duke researchers affects the Tph2 gene, built of some 100,000 nucleotide pairs.



The study also confirms that the Tph2 enzyme is critical for making brain serotonin, said Xiaodong Zhang, Ph.D., study co-author and an assistant professor at the Duke-NUS Graduate Medical <A class=iAs style="FONT-WEIGHT: normal; FONT-SIZE: 100%; PADDING-BOTTOM: 1px; COLOR: darkgreen; BORDER-BOTTOM: darkgreen 0.07em solid; BACKGROUND-COLOR: transparent; TEXT-DECORATION: underline" href="http://www.webwire.com/ViewPressRel.asp?aId=58216#" target=_blank itxtdid="5319385">School</A> Singapore. The results imply that humans with this mutation may have serious deficits in brain serotonin, he said.



In addition to revealing new clues to serotonin signaling in the brain, the Tph2-mutant mice could also serve as an animal model of drug-resistant depression. The Duke researchers have patented the strain of mice used in the study, said senior study author Marc Caron, Ph.D., James B. Duke professor of cell biology.



"These animals may be one of the better models for preclinical studies" Caron said. "We now have an animal model that mimics many of the things you would expect of people that are depressed"



Collaborators on the study include Ramona Rodriguiz, Tatyana Sotnikova, Michael Cools, William Wetsel and Raul Gainetdinov, all of Duke.


&nbsp;

<FONT size=2>Today I am one depressed mouse.</FONT>

Last edited by Ch_Isp_Morse on February 5th, 2008, 11:58 am, edited 1 time in total.
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Joined: January 1st, 1970, 12:00 am

February 5th, 2008, 5:10 pm #6

cutely depressesed
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Joined: April 1st, 2004, 4:56 pm

February 5th, 2008, 5:55 pm #7

kind of an Atypical depressed mouse
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Joined: January 1st, 1970, 12:00 am

February 5th, 2008, 10:05 pm #8


a friend.



<FONT color=#810081>http://news.nationalgeographic.com/news ... og_big.jpg</FONT><A href="http://news.nationalgeographic.com/news ... g.jpg"></A>

(photo apparently from India, frog helping mouse to survive in a monsoon).

&nbsp;

&nbsp;
Last edited by peagee on February 5th, 2008, 10:06 pm, edited 1 time in total.
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