Rett-icent Neurological Disorder Reveals Some Secrets
8 February 2006. Rett syndrome is a rare neurodevelopmental disorder that has been linked to autism (see Shibayama et al., 2004) and at least one incidence of childhood-onset schizophrenia (see Cohen et al., 2002). In most cases the syndrome can be traced to loss-of-function mutations in the gene coding for methyl-CpG binding protein 2 (Mecp2), a multitasker that both represses transcription and regulates mRNA splicing (see SRF related news story). However, beyond this detailed job description, it is still unclear why Mecp2 mutations cause this devastating disease. In the February 2 Neuron, Rudolph Jaenisch and colleagues at the Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, offer an explanation that at first blush appears to be counterintuitive. They report that Rett-like symptoms in mice harboring mutations in the repressor correlate with reduced levels of brain-derived neurotrophic factor (BDNF), rather than increased levels of the neurotrophin as one might expect. The findings indicate that the wild-type repressor somehow boosts BDNF in the normal brain and suggest that elevating the neurotrophin may be a therapeutic strategy to help patients suffering from the disease. In fact, by overexpressing BDNF, Jaenisch and colleagues were able to slow the onset and reduce the severity of disease in Mecp2 mutant mice. Curiously, both reductions in BDNF (see Durany et al., 2001) and BDNF-positive neurons (see Iritani et al., 2003) have also been linked to schizophrenia.
Two years ago, Jaenisch and colleagues reported that wild-type Mecp2 shuts off BDNF transcription (see Chen et al., 2003). This is what makes the current finding so interesting, because one would expect that to restore normal neurodevelopment in Mecp2 mutant mice—which lack the methyl CpG binding domain—one would have to decrease BDNF levels. But hints that the Mecp2/BDNF relationship may not be so simple came when the Jaenisch team began characterizing Mecp2 mutant animals. First author Qiang Chang and colleagues found that total brain BDNF dropped in these animals just when they started showing the first symptoms of disease, at around 6-8 weeks old.
To investigate this further, the researchers asked what would happen if they reduced BDNF in normal animals. Because BDNF knockouts are lethal, Chang and colleagues addressed this question by using BDNF conditional knockouts developed a few years ago in the Jaenisch lab. These animals retain the neurotrophin during embryonic development, but then lose it shortly after birth. Chang found that BDNF conditional knockout (cKO) mice recapitulated some of the symptoms of Mecp2 mutant mice, including low brain weight, reduced size of hippocampal CA2 neurons, and repetitive hind limb clasping, which is thought to mimic the hand-wringing behavior typically found in children with Rett’s. In addition, when Chang and colleagues crossed these cKO mice with Mecp2-negative animals, they found that the double knockout animals had a much shorter lifespan than wild-type or mice lacking only Mecp2. The double knockouts also had much earlier onset of locomotor symptoms.
If loss of BDNF mimics the effects of Mecp2 mutations, then might topping up levels of the neurotrophin not relieve some of the symptoms? This is exactly what Chang and colleagues found. When they made a conditional mutant mouse that overexpressed BDNF shortly after birth, then crossed this with Mecp2 mutant animals, the offspring, which produced around twice as much of the neurotrophin as normal, developed Rett-like symptoms later in life. They lived longer than the Mecp2 mutants, and the BDNF boost also increased their locomotor activity and brain weight.
The big question is why lack of the transcriptional repressor should lead to loss of BDNF in the brain in the first place, given that it has exactly the opposite effect in cultured neurons. The explanation for this seems to be related to experimental conditions. Chang and colleagues point out that in their initial experiments, the effect of Mecp2 on BDNF expression was measured in neurons that were artificially silenced. In the brain, however, neuronal activity is known to have a huge impact on BDNF expression. “Given that BDNF expression depends on neuronal activity, we favor the hypothesis that Mecp2 deficiency reduces neuronal activity, thereby indirectly causing a decreased BDNF protein level,” write the authors. In support of this, they found that the firing rate of neurons in layer five of the cortex is reduced in Mecp2 animals by about fourfold, and that overexpression of BDNF partly restored it. The next step will be to find out why Mecp2 mutations reduce neuronal activity.
Whether these latest findings have any specific relevance to schizophrenia is unclear. However, given that both BDNF and Mecp2 have been linked to various psychological and neurological disorders, the relationship between the two genes may well be worth following.—Tom Fagan.
Chang Q, Khare G, Dani V, Nelson S, Jaenisch R. The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression. Neuron February 2, 2006;49:341-348. Abstract
Comments on News and Primary Papers
Comment by: Mary Reid
Submitted 9 February 2006
Posted 10 February 2006
The suggestion by Rudolph Jaenisch and colleagues that decreased BDNF may in fact explain the brain pathology seen in Rett syndrome is most interesting.
I would like to propose that it is possible that Mecp2 mutations resulting in increased leptin levels may explain this. Melzner and colleagues (1) report that methyl-CpG binding proteins participate in transcriptional repression and regulation of the human leptin gene. Brunetti et al. (2) find that leptin inhibits depolarization-induced norepinephrine and dopamine release. Ivy and colleagues (3) find that noradrenergic and serotonergic blockade inhibits BDNF mRNA activation following exercise and antidepressant. Is it possible that increased leptin as a consequence of an Mecp2 mutation has resulted in reduced noradrenergic stimulation of BDNF transcription? The study by the Elefteriou group (4) reporting that elevating serum levels reduces bone mass, which is a characteristic of Rett syndrome, would seem to support the above hypothesis.
1. Melzner I, Scott V, Dorsch K, Fischer P, Wabitsch M, Bruderlein S, Hasel C, Moller P. Leptin gene expression in human preadipocytes is switched on by maturation-induced demethylation of distinct CpGs in its proximal promoter. J Biol Chem. 2002 Nov 22;277(47):45420-7. Epub 2002 Sep 3.
2. Brunetti L, Michelotto B, Orlando G, Vacca M. Leptin inhibits norepinephrine and dopamine release from rat hypothalamic neuronal endings. Eur J Pharmacol. 1999 May 21;372(3):237-40.
3. Ivy AS, Rodriguez FG, Garcia C, Chen MJ, Russo-Neustadt AA.
Noradrenergic and serotonergic blockade inhibits BDNF mRNA activation following exercise and antidepressant. Pharmacol Biochem Behav. 2003 Apr;75(1):81-8.
4. Elefteriou F, Takeda S, Ebihara K, Magre J, Patano N, Kim CA, Ogawa Y, Liu X, Ware SM, Craigen WJ, Robert JJ, Vinson C, Nakao K, Capeau J, Karsenty G.
Serum leptin level is a regulator of bone mass. Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3258-63. Epub 2004 Feb 20.
View all comments by Mary ReidComment by: Mary Reid
Submitted 13 March 2007
Posted 14 March 2007
I had proposed that mutations in MECP2 may result in increased leptin levels in Rett syndrome. I see that Blardi and colleagues report that patients with classic Rett syndrome and preserved-speech variant had leptin values significantly higher than controls. Ashwood et al. also report elevated leptin levels in those with early-onset autism.
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Related News: BDNF In the Nucleus Accumbens—Too Much of a Good Thing?Comment by: NN Kudryavtseva
Submitted 23 February 2006
Posted 23 February 2006
Berton and colleagues show very impressive data of molecular studies demonstrating numerous changes of gene expression in brain under repeated social defeats. However, the behavioral or pharmacological data that the authors use to support the development of depression in socially defeated mice may be interpreted otherwise.
The authors used decreases in the level of social communication (they called it avoidance-approach behavior) in defeated losers as parameters of depression. We repeatedly noted in our experiments on the social model of depression induced by social confrontations in mice of the C57BL/6J strain (Kudryavtseva et al., 1991) that even one or two social defeats lead to a decrease of communication in mice. Thus, avoidance behavior cannot be used as a specific parameter of depression; rather, it may represent anxiety. However, our experiments demonstrated that longer experience of defeats over 20-30 days (but not 10 days, as used by Berton et al.) in male mice produces development of a depression-like state (anxious depression): similarities of symptoms, etiological factors (social unavoidable emotional stress, permanent anxiety), sensitivity to chronic antidepressants and anxiolytics (imipramine, tianeptine, citalopram, fluoxetine, buspirone, etc.), as well as brain neurochemistry changes (serotonergic and dopaminergic systems) (Kudryavtseva et al., 1991; for reviews see Kudryavtseva, Avgustinovich, 1998; Avgustinovich et al., 2004).
In our molecular studies, we also demonstrated changes of gene expression in the brains of male mice after daily agonistic interactions. Three experimental groups were compared: the losers with repeated experience of social defeats; winners with repeated aggression accompanied by social victories; and controls (very important—the same strain). In has been shown that MAOA and SERT mRNA levels in the raphe nuclei of the losers were higher than in the controls and winners. TH and DAT gene expression in the ventral tegmental area was higher and κ opioid receptor gene expression was lower in the winners in comparison with the losers and controls (see Filipenko et al., 2001; 2002; Goloshchapov et al., 2005; reviewed in Kudryavtseva et al., 2004). Thus, there are different specific changes in gene expression in different brain areas in male mice with opposite social behaviors—winners and losers.
As for BDNF, there is an emerging body of data suggesting that different mood disorders are associated with changed BDNF. I think that changes of BDNF gene expression in the losers may be nonspecific for depression state. Expression of the BDNF gene in the winners should be investigated to confirm or reject this idea.
Again, Berton et al. (2006) have demonstrated very impressive data. Taking into consideration these data and our molecular studies, it may be suggested that the sensory contact paradigm (sensory contact model) may be used for the study of association between agonistic behavior and gene expression. We called this scientific direction “From behavior to gene” (reviewed in Kudryavtseva et al., 2004), as an addition to the traditional “From gene to behavior.”
Kudryavtseva NN, Bakshtanovskaya IV, Koryakina LA. Social model of depression in mice of C57BL/6J strain.
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Filipenko ML, Alekseyenko OV, Beilina AG, Kamynina TP, Kudryavtseva NN. Increase of tyrosine hydroxylase and dopamine transporter mRNA levels in ventral tegmental area of male mice under influence of repeated aggression experience.
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Avgustinovich DF, Alekseenko OV, Bakshtanovskaia IV, Koriakina LA, Lipina TV, Tenditnik MV, Bondar' NP, Kovalenko IL, Kudriavtseva NN. [Dynamic changes of brain serotonergic and dopaminergic activities during development of anxious depression: experimental study]
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Goloshchapov AV, Filipenko ML, Bondar NP, Kudryavtseva NN, Van Ree JM. Decrease of kappa-opioid receptor mRNA level in ventral tegmental area of male mice after repeated experience of aggression.
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View all comments by NN Kudryavtseva