DISCUSSION AND CONCLUSIONS
The regulation of gene expression occurs at different levels, from DNA to protein, and through various mechanisms. Chromatin remodelling is involved in the definition of transcriptional active and inactive regions of the chromosomes. Posttranslational modifications of histone tails in the chromatin mechanisms can cause the chromatin remodelling. Abnormal regulation of gene expression by epigenetic modifications often causes neurological and behavioural deficits in human diseases and in their mouse models, suggesting a relevant function for chromatin remodelling in the proper function of the central nervous system. This thesis investigated the epigenetic mechanisms correlated to normal brain functional states, such as during development of visual plasticity. In addition, we studied the Rett syndrome, a human disorders caused by alterations of epigenetic mechanisms.
In the first part of discussion we will focus on the results obtained about the regulation of experience-dependent, chromatin remodelling occurring in the visual cortex during the critical period and in adult mice. The second part of discussion will deal with the results obtained in MeCP2 mutants modelling RTT.
Chapter 8: Visual system: different regulation of signaling
pathways during the development
In the visual cortex, visual experience is crucial during the critical period of development. At molecular level, signalling cascades regulate visual plasticity in the young and in the adult cortex.
Our results showed that visual experience differently activates intracellular signaling pathways that control gene expression in the visual cortex of juvenile and adult mice.
Visual stimulation during the Critical Period causes ERK-Dependent Histone Acetylation and Phosphorylation
Previous data (Cancedda et al. 2003; Putignano et al., 2007) demonstrated that ERK, MSK, and CREB -mediated gene expression were strongly activated by visual experience during the critical period. We found that visual experience during the critical period activates ERK-dependent posttranslational modifications of histones associated with chromatin rearrangement and CREB-mediated gene expression.
Acetylation and phosphorylation of histones are mechanisms that control chromatin structure. Several studies have demonstrated that regulation of gene expression through posttranslational modifications of histones is also present in neurons. For instance, epigenetic directly modulates the expression of the molecular components of the circadian clock. Namely, the acetylation of histones H3 and H4 is correlated to promoters of genes responsible for molecular clock mechanism, regulating differentially the expression of genes during a circadian rhyme. The infusion of trichostatin A (an inhibitor of deacetylase) into the suprachiasmatic nucleus increases the expression of the mouse clock genes period 1 (Per1) and Per2 (Naruse et al., 2004).
Histone acetylation also controls transcription of genes required for consolidation of long-term memory and LTP(Levenson et al., 2004). Indeed, acetylation of histone H3, but not H4, is significantly increased in contextual fear conditioning tests. Several studies have shown that acetylation of histones is important for the consolidation of term memories and that disruption of the activity of HATs interferes with long-term memory formation. Indeed, transgenic mice with impaired CBP (CREB-binding
protein) function that has endogenous HAT, show significant deficits in various forms of long-term memory (Alarcón et al., 2004).
Plasticity-induced epigenetic changes are also observed in mammalian models of synaptic plasticity. Several forms of LTP require the activation of NMDA receptors and activation of the MEK–ERK/MAPK signalling cascade. For example it has been shown in the hippocampus that activation of NMDA receptors induce an increase in the acetylation of histone H3.
Our data indicate that experience-dependent regulation of chromatin structure can be an important mechanism of regulation of gene expression in the developing visual cortex as well. Our result show that during the critical period, visual stimulation causes an activation of phosphoacetylation of H3 and acetylation of H4 histones. In addition, the phosphoryation of H3 is ERK dependent. Previous data demonstrated that ERK kinase was strongly activated by visual experience during the critical period (Cancedda et al. 2003; Putignano et al., 2007). The action of ERK on H3 phosphorylation can be mediated by various kinases, including MSK. MSK kinase is required for CREB and H3 phosphorylation in neuronal cells in response to various stimuli, such as neurotrophins and cocaine (Arthur et al., 2004; Brami-Cherrier et al., 2005). Many studies on cell lines have proven MSK ability to phosphorylate CREB and H3. MSK is activated by visual stimulation and its activation is prevented by ERK inhibitors in visual cortices of juvenile mice (Putignano et al. 2007). Putignano et al. (Putignano et al. 2007) also observed that cells positive for activated ERK were positive for activated MSK. Our results in visual cortices of juvenile mice, showed that cells positive for activated MSK were also positive for phosphorylated H3. These data indicate that an ERK-MSK-H3 pathway is activated by visual experience in the developing visual cortex and that these biochemical events occur in the same cell.
Our results show that visual experience caused an increase of acetylation H3 and H4 histones in juvenile mice. Which one could be the possible mediators of the effects of visual stimulation on H3 acetylation? Although additional studies are required to unravel the molecular cascade linking ERK to histone acetylation, it is possible that the latter is due to the activity-dependent recruitment to chromatin of transcriptional coactivators such as CBP, endowed with acetyltransferase activity. ERK can phosphorylate CBP in vitro (Janknecht and Nordheim, 1996); however, a direct action of ERK on CBP seems dispensable for NMDA-induced CBP phosphorylation (Impey et al., 2002). Thus, ERK could be required for histone acetylation, because of its role in
regulating the formation of a CREB-CBP transcriptional complex that recruits CBP to chromatin and allows histone acetylation by CBP. The requirement of ERK for visually stimulated histone acetylation does not exclude other kinases from contributing to this signaling pathway by interacting with ERK-regulated mechanisms. For instance, CBP phosphorylation by CaMKIV is crucial for activity-dependent gene transcription in cortical cultures (Impey et al., 2002). PKA also plays an important role in synaptic plasticity of the visual cortex and regulates CREB-mediated gene expression (Beaver et al., 2001; Cancedda et al., 2003). Previous studies show that inhibition of PKA substantially reduces visually stimulated activation of ERK, suggesting that at least part of the effects of PKA on visual cortical plasticity could be mediated by ERK (Cancedda et al., 2003). Earlier experiments showed that visual experience in juvenile mice induces phosphorylation of the transcription factor CREB and causes CREB-mediated gene expression (Cancedda et al., 2003). We analyzed the expression of miRNA132 and BDNF, two endogenous transcripts that are important in synaptic plasticity and that are regulated by CREB. Our results indicate that visual experience causes an increase of these transcripts in juvenile mice suggesting that the visual induction of transcription previously observed using the CRE-lacZ mice could be present also on endogenous CREB promoters.
Regulation of Visually Stimulated Gene Transcription in adult mice
Defective visual experience during the critical period of postnatal development causes dramatic alterations in the functional organization of the visual cortex, resulting in poor vision of the affected eye (amblyopia). This observation indicates that visual experience is important in the mechanisms of development of cortical circuits. Although experience dependent plasticity is present in the adult visual cortex (Karmarkar et Dan, 2006), the manipulations of visual inputs, such as monocular deprivation, do not cause effects in adult animals and might be mediated by different mechanisms (Sawtellet al., 2003). At the end of the critical period, a reduction of synaptic plasticity occurs. Adult animals do not achieve normal vision after periods of deprivation initiated during the critical period (Prusky et al., 2000; Pizzorusso et al., 2006). Several mechanisms, such as the modifications of extracellular matrix composition and maturation of intracortical myelination, which could inhibit structural plasticity (Pizzorusso et al., 2002; McGee et
al., 2005), and maturation of inhibitory circuitry (Huang et al., 1999; Hensch, 2005) are thought to make the excitatory-inhibitory balance less favourable to plasticity.
Our results show that visual experience differently activates intracellular signaling pathways in the visual cortex of juvenile and adult mice. In addition, we show that developmental down regulation of visually stimulated gene transcription taking place in adult mice might regulate the developmental reduction of plasticity occurring in the adult visual cortex.
Downregulation of experience-dependent posttranslational modifications of CREB, H3, and H4, but not MSK, in Adult Mice
We observed a substantial reduction of the effects of visual stimulation on CREB phosphorylation, on histone phsphoacetylation and on CRE-mediated gene expression in adult animals. Also, Pham et al. (Pham et al. 1999) showed that CREB-mediated gene expression is induced in the visual cortex following monocular deprivation and declines in adulthood. As opposed to CREB, our data indicate that the effects of visual stimulation on ERK and MSK were similar in juvenile and adult mice. Therefore the closure of the critical period is associated with a decrease in the ability of visual experience to drive changes in histone phosphorylation and acetylation that control gene transcription.
It has been shown in the hippocampus that regulation of transcription through histone posttranslational modifications is involved in regulating the production of transcripts necessary for consolidation of long-term changes of synaptic efficacy (Alarcon et al., 2004; Korzus et al., 2004; Levenson et al., 2004; Wood et al., 2006). Therefore it is conceivable that the reduced activation of experience-dependent signalling leading to synaptic plasticity in coincidence with critical period closure could be a factor contributing to the developmental reduction of plasticity in the visual cortex. Putignano et al. showed that increasing histone acetylation in adult animals by trichostatin A, an inhibitor of deacetylase, promoted experience-dependent plasticity of the adult visual cortex. Electrophysiological evidence demonstrated that the trichostatin treatment promoted ocular dominance plasticity in the adult mouse.
Different mechanisms have been proposed to be at the basis of critical period onset and offset, including changes in brain circuitry and molecular modifications of extracellular factors like CSPGs and Nogo (McGee, et al., 2005). Our data indicate that
developmental plasticity in the visual cortex is controlled at different levels also comprising those factors regulating experience-dependent gene transcription.
Chapter 9: Prevention of synaptic alterations and improvement
of behavioural deficits of MeCP2 null mice by early
environmental stimulation
Histone acetylation is regulated by acetyltransferases and deacetylases recruited to chromatin by interaction with DNA proteins. Recent progress in the field of chromatin remodelling and transcriptional regulation has dramatically changed our understanding of the ways in which genes are regulated. Epigenetic modifications are important in neurological disorders such as Rubinstein–Taybi syndrome (RTS) and RTT. For example, RTS is caused by mutations of the CREB-binding protein CBP, endowed with histone acetyltransferase activity. In this disease, an abnormal regulation of epigenetic mechanisms can causes severe deficits, evident in the long-term memory.
Mutations of MeCP2, a protein that interacts with methylated DNA and histone deacetylases, cause the majority of RTT cases. In mice, mutations of MeCP2 cause a range of effects reminiscent of the symptoms observed in patients, including motor impairments, cognitive and emotional abnormalities (Chen et al., 2001; Guy et al., 2001; Shahbazian et al., 2002; Pelka et al., 2006). We used electron microscopy, electrophysiological, biochemical and behavioural techniques to investigate whether early EE of MeCP2 null mice rescue molecular, synaptic, motor, emotional and cognitive abnormalities, and whether it is effective in increasing cortical BDNF levels. We found that early EE promotes synaptic plasticity and enhances synapse formation in the cerebral cortex of MeCP2y/- mice. Increased synaptic density was observed also in
the cerebellar cortex. Morphological improvement was associated to increased cortical BDNF levels. Behaviourally, EE strongly enhanced motor coordination and motor learning in MeCP2y/- mice. These results show that MeCP2 is not strictly required for synaptic plasticity and suggest that preservation of morphological and functional synaptic plasticity is a key mechanism underlying the beneficial effects of EE on MeCP2 mutants.
Synaptic effects of EE in MeCP2 mutants
Although the cellular mechanisms that translate alterations in MeCP2 function into RTT symptoms are still obscure, a series of observations from several laboratories lead to the
hypothesis that RTT is a disorder of synaptic development (Zoghbi; 2003). Anatomically, the brains of RTT patients and MeCP2 null mice appear without gross morphological abnormalities. However, both animal models and human RTT patients exhibit a reduction in brain size, accompanied by neurons that are abnormally small and densely packed, with markedly shortened and simplified dendritic arbors. Several neurochemical studies also evidenced that glutamate mediated neurotransmission is disrupted in RTT. In MeCP2 null mice, hippocampal neurons display a strong reduction in synaptic response to glutamate. These studies indicate the occurrence of alterations in synaptic function and morphology in neurons of MeCP2 mutants (Collins et al., 2004; Kishi and Macklis, 2004; Dani et al., 2005; Asaka et al., 2006; Nelson et al., 2006). In addition, it has been found that at as early as 2 weeks of age, pyramidal neurons recorded in S1 slices from MeCP2 mutant mice are less active. The discovery of a precocious synaptic alteration in MeCP2 mutants suggests that the regulation of the initial formation of synaptic contacts could be a primary function of MeCP2.
Our analysis of excitatory synapses in the somatosensory and cerebellar cortex of MeCP2y/- mice aged P52 showed a reduction of synapse number that does not reach statistical significance. Chao et al., (Chao et al., 2007) suggested that in vivo changes in synapse numbers in the hippocampus observed during postnatal development are due to homeostatic compensatory change occurring in response to the early perturbation of synapse number. It is possible that, similarly to the hippocampus, an initial synaptic deficit exists in the somatosensory and cerebellar cortex of MeCP2y/- mice, but it undergoes late homeostatic compensation (Chao et al., 2007). Another intriguing possibility is that structural alterations selective for a specific neuronal population are masked in our EM analyses by data from other neuronal populations that remain unaffected.
Synaptic plasticity is also impaired in MeCP2 null mice and LTP is reduced in cortical slices (Asaka et al., 2006) while cortical and hippocampal slices obtained from the Mecp2308/Ymice (with a truncated form of MeCP2) show a reduction of LTP (Moretti et al., 2006). Our data demonstrate the presence of a deficit of LTP in MeCP2y/- mice that could be rescued by EE. The improvement in functional plasticity by EE was accompanied by the activation of mechanisms of structural plasticity, resulting in a strong increase of synaptic density in the cerebral and cerebellar cortex of EE MeCP2 y/-mice. These data suggest that MeCP2 plays a regulatory role in synaptic plasticity but it is not essential for experience-dependent regulation of synaptic strength.
The actions of EE can be mediated by several molecular mechanisms, including augmentation of BDNF expression (van Praag et al., 2000). Several studies (Chang et al. 2006) have shown a reduction of BDNF levels in extracts of brain from knockout MeCP2 compared to the wild-type. In addition, it has been demonstrated that over-expression of BDNF in MeCP2 knockout mouse, improves locomotor functions and extends lifespan of MeCP2 mutants mice. We confirmed previous data (Chang et al. 2006)) showing that MeCP2y/- mice have reduced cortical and cerebellar BDNF levels with respect to WT, but we found that EE could significantly raise BDNF levels in the cortex of MeCP2y/- mice. On the contrary, EE did not cause an increase of BDNF levels in the cerebellum of both wild-type and MeCP2y/- mice. This is in agreement with the results by Kondo et al. (Kondo et al., 2008) indicating an increase of BDNF levels by postweaning EE in the hippocampus, but not in the cortex and cerebellum of female MeCP2 mutants. Thus, it is conceivable that the heightened neuronal activity induced by EE can be transduced at nuclear level into increased BDNF protein in brain of MeCP2y/- mice, however, further studies are necessary to understand why different brain areas display different responses to EE.
At a molecular level, we investigated whether deficits of regulation of protein synthesis occur in MeCP2y/- mice. We analyzed the phosphorylation of S6 kinase involved in the translation of several mRNAs, presumably by mediating the multiple phosphorylation of 40S ribosomal protein S6, thus providing an increased protein synthesis capacity. We detected a striking reduction of phosphorylation of S6 at Ser235/236 in the cortex and cerebellum of MeCP2y/- mice. Although the mechanisms ultimately linking the MeCP2 mutation to the mouse phenotype are still obscure, these results open a new possibility of interpretation. In addition, these data prompt further studies analyzing whether agents potentiating the mTOR pathway could rescue at least part of the phenotype of MeCP2 mutants.
Effects of EE in MeCP2+/- mice
Although MeCP2 y/- mice are widely employed to assess the extreme effects of MeCP2 mutation, female MeCP2 +/- mice more closely recapitulate the characteristics of RTT individuals. Female Mecp2+/- mice (carrying one copy of normal allele) have behavioural abnormalities similar to those of the male MeCP2 mutants, but with a later
age of onset. In female Mecp2 +/- mice, progressive motor impairments develop slowly during adulthood, making it possible to test more complex behaviours with minimal interference from motor impairments. Using young female MeCP2+/- mice, we
investigated the effects of EE on alteration of cognitive performance and anxiety, two clinical symptoms of RTT. Previous work found that MeCP2+/-mice show an alteration in learning and memory in the object recognition test (Stearns et al., 2007) while MeCP2308/y mice, that have residual MeCP2 function, are impaired in the Morris water maze when tested with a mild learning protocol (Moretti et al., 2006). Increased anxiety-related behaviour has been observed in female MeCP2+/- mice (Stearns et al., 2007; Jugloff et al., 2008) and in MeCP2308/y (McGill et al., 2006). In addition, MeCP2 mutants showed altered expression of genes involved in stress responses (Nuber et al., 2005; McGill et al., 2006). Our findings show that MeCP2+/- female mice are impaired in the Morris water maze and display increased anxiety-related behaviour in the open field. Importantly, EE could completely prevent the behavioural alterations of MeCP2 +/-mice, suggesting that environmental stimulation could have positive effects also on those pathological aspects of RTT involving learning and memory, and emotional behaviour.
Our study indicates that early environmental stimulation improves several phenotypic features of female MeCP2+/- and male MeCP2y/- mutants. A previous study (Kondo et al. 2008) showed that postweaning EE ameliorates motor coordination in heterozygous females but not in males. In addition, the authors detected an increase of BDNF level in the hippocampus, but not in the cortex and cerebellum of the female mice. Male mice showed no effects of postweaning EE on cerebellar BDNF.
A possible reason for the efficacy of our EE protocol on MeCP2y/- mice could be the
early beginning of EE (P10). Synaptic defects are already present in MeCP2y/- mice at
two weeks of age (Chao et al., 2007) and motor symptoms can be observed as early as three-four weeks. Thus, early environmental stimulation could be particularly effective in balancing the initial pathogenetic mechanisms occurring during early postnatal development
Recently, it has been demonstrated that the introduction of a copy of the MECP2 transgene into MeCP2 null mice, so that MeCP2 protein levels become normal, rescues neurological abnormalities of these nulls. Actually, Guy et al. (Guy et al., 2007) and Giacometti et al. (Giacometti et al.2007) observed disease reversibility in mouse models of RTT. Intriguingly, the beneficial action of our EE protocol seems to have different
properties other than the effects of genetic reactivation of MeCP2 expression in MeCP2y/- mice. Indeed, MeCP2 reactivation is effective even at relatively late stages of disease progression and results in increased lifespan (Guy et al., 2007). EE has maximal effects if begun early and it is minimally effective on animal survival suggesting that its action is not due to activation of molecular mechanisms mimicking MeCP2 action. Possibly, EE involves potentiation of compensatory neuronal capabilities implicating increased BDNF expression. Extrapolating our results to humans it is reasonable to postulate that early rehabilitative intervention after early diagnosis would achieve the best results in RTT patients.
REFERENCES
Alarcón JM, Malleret G, Touzani K, Vronskaya S, Ishii S, Kandel ER, Barco A (2004)
Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration.
Neuron. 2004 Jun 24;42(6):947-59.
Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) RTT is caused by mutations in X-linked MECP2, encoding methyl-CpGbinding protein 2. Nat Genet 23:185-188.
Armstrong, D.D. (2005). Neuropathology of RTT. J. Child. Neurol. 20, 747–753.
Arthur, J.S., Fong, A.L., Dwyer, J.M., Davare, M., Reese, E., Obrietan, K., and Impey, S. (2004). Mitogen- and stress-activated protein kinase 1 mediates cAMP response element-binding protein phosphorylation and activation by neurotrophins. J. Neurosci. 24, 4324–4332.
Asaka Y, Jugloff DG, Zhang L, Eubanks JH, Fitzsimonds RM (2006)
Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of RTT. Neurobiol. Dis 21:217-227.
Beaver, C.J., Ji, Q., Fischer, Q.S., and Daw, N.W. (2001).
Cyclic AMP-dependent protein kinase mediates ocular dominance shifts in cat visual cortex.
Nat. Neurosci.4, 159–163
Bear MF, Kleinschmidt A, Gu QA, Singer W.
Disruption of experience-dependent synaptic modifications in striate cortex by infusion of an NMDA receptor antagonist.
Benaroya-Milshtein N, Hollander N, Apter A, Kukulansky T, Raz N, Wilf A, Yaniv I, Pick CG.(2004)
Environmental enrichment in mice decreases anxiety, attenuates stress responses and enhances natural killer cell activity.
Eur. J. Neurosci. 20, 1341–1347 (2004).
Bennett, J. C., McRae, P. A., Levy, L. J. & Frick, K. M. (2006).
Long-term continuous, but not daily, environmental enrichment reduces spatial memory decline in aged male mice.
Neurobiol. Learn. Mem. 85, 139–152 (2006).
Berardi, N., Pizzorusso, T., and Maffei, L. (2000). Critical periods during sensory development.
Curr. Opin. Neurobiol. 10, 138–145.
Berardi N, Braschi C, Capsoni S, Cattaneo A, Maffei L. (2007)
Environmental enrichment delays the onset of memory deficits and reduces neuropathological hallmarks in a mouse model of Alzheimer-like neurodegeneration. J Alzheimers Dis. 2007 Jun;11(3):359-70.
Bertani, I., Rusconi, L., Bolognese, F., Forlani, G., Conca, B., De Monte, L., Badaracco, G., Landsberger, N., and Kilstrup-Nielsen, C.(2006).
Functional consequences of mutations in CDKL5, an X-linked gene involved in infantile spasms and mental retardation.
J. Biol. Chem. 281, 32048–32056.
Bezard E, Dovero S, Belin D, Duconger S, Jackson-Lewis V, Przedborski S, Piazza PV, Gross CE, Jaber M.
Enriched environment confers resistance to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and cocaine: involvement of dopamine transporter and trophic factors.
Bienvenu T, Chelly J (2006)
Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized Nature Reviews Genetics 7, 415 - 426 (01 Jun 2006)
Brami-Cherrier, K., Valjent, E., Herve, D., Darragh, J., Corvol, J.C., Pages, C., Arthur, S.J., Girault, J.A., and Caboche, J. (2005).
Parsing molecular and behavioral effects of cocaine in mitogen- and stress activated protein kinase-1-deficient mice.
J. Neurosci. 25, 11444–11454
Cancedda L, Putignano E, Impey S, Maffei L, Ratto GM, Pizzorusso T.(2003) Patterned vision causes CRE-mediated gene expression in the visual cortex through PKA and ERK.
J Neurosci. 2003 Aug 6;23(18):7012-20.
Cancedda L, Putignano E, Sale A, Viegi A, Berardi N, Maffei L.(2004) Acceleration of visual system development by environmental enrichment. J Neurosci. 2004 May 19;24(20):4840-8
Cannell IG, Kong YW, Bushell M.(2008) How do microRNAs regulate gene expression? Biochem Soc Trans. 2008 Dec;36(Pt 6):1224-31.
Chahrour M, Zoghbi HY (2007)
The story of RTT: from clinic to neurobiology. Neuron 56:422-437.
Chahrour M, Jung SY, Shaw C, Zhou X, Wong ST, Qin J, Zoghbi HY (2008) MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320:1224-1229.
Chandramohan Y, Droste SK, Arthur JS, Reul JM. (2008)
The forced swimming-induced behavioural immobility response involves histone H3 phospho-acetylation and c-Fos induction in dentate gyrus granule neurons via activation of the N-methyl-D-aspartate/extracellular signal-regulated kinase/mitogen- and stress-activated kinase signalling pathway.
Eur J Neurosci. 2008 May;27(10):2701-13
Chang Q, Khare G, Dani V, Nelson S, Jaenisch R (2006)
The disease progression of MeCP2 mutant mice is affected by the level of BDNF expression.
Neuron 49:341-348.
Chao HT, Zoghbi HY, Rosenmund C (2007)
MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number.
Neuron 56:58-65.
Chen A, Muzzio IA, Malleret G, Bartsch D, Verbitsky M, Pavlidis P, Yonan AL, Vronskaya S, Grody MB, Cepeda I, Gilliam TC, Kandel ER (2003)
Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins.
Neuron. 2003 Aug 14;39(4):655-69
Chen, R.Z., Akbarian, S., Tudor, M., and Jaenisch, R. (2001).
Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice.
Nat. Genet. 27, 327–331
ChenW.G., Chang, Q., Lin, Y.,Meissner, A., West, A.E., Griffith, E.C., Jaenisch, R., and Greenberg, M.E. (2003).
Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2.
Collins, A.L., Levenson, J.M., Vilaythong, A.P., Richman, R., Armstrong, D.L., Noebels, J.L., David Sweatt, J., and Zoghbi, H.Y. (2004).
Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum. Mol. Genet. 13, 2679–2689.
Dani VS, Chang Q, Maffei A, Turrigiano GG, Jaenisch R, Nelson SB (2005)
Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of RTT.
Proc Natl Acad Sci U S A 102:12560-12565.
Dierssen M, Benavides-Piccione R, Martínez-Cué C, Estivill X, Flórez J, Elston GN, DeFelipe J.
Alterations of neocortical pyramidal cell phenotype in the Ts65Dn mouse model of Down syndrome: effects of environmental enrichment.
Cereb Cortex. 2003 Jul;13(7):758-64.
Di Cristo G, Berardi N, Cancedda L, Pizzorusso T, Putignano E, Ratto GM, Maffei (2001)
Requirement of ERK activation for visual cortical plasticity. Science 292, 2337–2340
Dragich, J.M., Kim, Y.H., Arnold, A.P., and Schanen, N.C. (2007).
Differential distribution of the MeCP2 splice variants in the postnatal mouse brain. J. Comp. Neurol. 501, 526–542.
Duffy, S. N., Craddock, K. J., Abel, T. & Nguyen, P. V. (2001)
Environmental enrichment modifies the PKAdependence of hippocampal LTP and improves hippocampus-dependent memory.
Learn. Mem. 8, 26–34 (2001).
Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, Kwiatkowski DJ, Ramesh V, Silva AJ. (2008)
Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat Med. 14(8):843−8.
Fagiolini, M. and Hensch, T.K. (2000)
Inhibitory threshold for criticalperiod activation in primary visual cortex. Nature 404, 183–186
Feldman, D.E. (2000) Inhibition and plasticity. Nat. Neurosci. 3, 303–304
Flavell SW, Greenberg ME. (2008)
Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system.
Annu Rev Neurosci. 2008;31:563-90
Francis DD, Meaney MJ (1999)
Maternal care and the development of stress responses. Curr Opin Neurobiol 9:128-134.
Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai LH.(2007)
Recovery of learning and memory is associated with chromatin remodelling. Nature. 2007 May 10;447(7141):178-82
Giacometti E, Luikenhuis S, Beard C, Jaenisch R (2007)
Partial rescue of MeCP2 deficiency by postnatal activation of MeCP2. Proc Natl Acad Sci U S A 104:1931-1936.
Ginty DD, Bonni A, Greenberg ME.(1994)
Nerve growth factor activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB.
Cell. 1994 Jun 3;77(5):713-25.
Grosso, S., Brogna, A., Bazzotti, S., Renieri, A., Morgese, G., and Balestri, P. (2007).
Seizures and electroencephalographic findings in CDKL5 mutations Brain Dev. 29, 239–242.
Guan, Z., Giustetto, M., Lomvardas, S., Kim, J.H., Miniaci, M.C., Schwartz, J.H., Thanos, D., and Kandel, E.R. (2002).
Integration of long-term-memory related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure.
Cell 111, 483–493.
Guy J, Hendrich B, Holmes M, Martin JE, Bird A (2001)
A mouse Mecp2-null mutation causes neurological symptoms that mimic RTT. Nat Genet 27:322-326.
Guy J, Gan J, Selfridge J, Cobb S, Bird A (2007)
Reversal of neurological defects in a mouse model of RTT. Science 315:1143-1147.
Hamberger A, Gillberg C, Palm A, Hagberg B (1992) Elevated CSF. Glutamate in RTT.
Neuropediatrics 1992;23:212–213.
Hanover JL, Huang ZJ, Tonegawa S, Stryker MP.(1999)
Brain-derived neurotrophic factor overexpression induces precocious critical period in mouse visual cortex.
J Neurosci. 1999 Nov 15;19(22):RC40.
Hebert, A. E. & Dash, P. K. (2002)
Extracellular signal-regulated kinase activity in the entorhinal cortex is necessary for longterm spatial memory.
Learn. Mem. 9, 156–166 (2002).
Hensch TK, Fagiolini M, Mataga N, Stryker MP, Baekkeskov S, Kash SF.(1998) Local GABA circuit control of experiencedependent plasticity in developing visual cortex.
Hensch, T.K. (2005).
Critical period plasticity in local cortical circuits. Nat. Rev. Neurosci. 6, 877–888.
Hong Joo Kim & Dafna Bar-Sagi(2004)
Modulation of signalling by Sprouty: a developing story Nature Reviews Molecular Cell Biology 5, 441-450 (June 2004)
Huang, Z.J., Kirkwood, A., Pizzorusso, T., Porciatti, V., Morales, B., Bear, M.F., Maffei, L., and Tonegawa, S. (1999).
BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex.
Cell 98, 739–755
Hofer SB, Mrsic-Flogel TD, Bonhoeffer T, Hübener M.
Lifelong learning: ocular dominance plasticity in mouse visual cortex. Curr Opin Neurobiol. 2006 Aug;16(4):451-9.
Ickes BR, Pham TM, Sanders LA, Albeck DS, Mohammed AH, Granholm AC. (2000)
Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain.
Exp. Neurol. 164, 45–52 (2000).
Impey, S., Mark, M., Villacres, E.C., Poser, S., Chavkin, C., and Storm, D.R. (1996).
Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus.
Neuron16, 973–982.
Impey, S., Fong, A.L., Wang, Y., Cardinaux, J.R., Fass, D.M., Obrietan, K., Wayman, G.A., Storm, D.R., Soderling, T.R., and Goodman, R.H. (2002).
Phosphorylation of CBP mediates transcriptional activation by neural activity and CaM kinase IV.
Janknecht, R., and Nordheim, A. (1996).
MAP kinase-dependent transcriptional coactivation by Elk-1 and its cofactor CBP. Biochem. Biophys. Res. Commun. 228, 831–837.
Jankowsky JL, Melnikova T, Fadale DJ, Xu GM, Slunt HH, Gonzales V, Younkin LH, Younkin SG, Borchelt DR, Savonenko AV. (2005).
Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer’s disease.
J. Neurosci. 25, 5217–5224 (2005).
Jaworski J, Sheng M. (2006)
The growing role of mTOR in neuronal development and plasticity. Mol Neurobiol. 34(3):205−19.
Jugloff DG, Vandamme K, Logan R, Visanji NP, Brotchie JM, Eubanks JH (2008) Targeted delivery of an Mecp2 transgene to forebrain neurons improves the behavior of female Mecp2-deficient mice.
Hum Mol Genet 17:1386-1396
Karmarkar, U.R., and Dan, Y. (2006).
Experience-dependent plasticity in adult visual cortex. Neuron 52, 577–585
Kishi N, Macklis JD (2004)
MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions.
Mol Cell Neurosci 27:306-321.
Kondo M, Gray LJ, Pelka GJ, Christodoulou J, Tam PP, Hannan AJ (2008)
Environmental enrichment ameliorates a motor coordination deficit in a mouse model of RTT--Mecp2 gene dosage effects and BDNF expression
Korzus, E., Rosenfeld, M.G., and Mayford, M. (2004).
CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42, 961–972.
Lappalainen R, Riikonen RS.(1996)
High levels of cerebrospinal fluid glutamate in RTT. Pediatr Neurol 1996;15:213–216.
Lazarov O, Robinson J, Tang YP, Hairston IS, Korade-Mirnics Z, Lee VM, Hersh LB, Sapolsky RM, Mirnics K, Sisodia SS.(2005)
Environmental enrichment reduces Aβ levels and amyloid deposition in transgenic mice.
Cell 120, 701–713 (2005).
Leggio MG, Mandolesi L, Federico F, Spirito F, Ricci B, Gelfo F, Petrosini L.(2005)
Environmental enrichment promotes improved spatial abilities and enhanced dendritic growth in the rat.
Behav. Brain Res. 163, 78–90 (2005).
Levenson, J.M., O’Riordan, K.J., Brown, K.D., Trinh, M.A., Molfese, D.L., and Sweatt, J.D. (2004).
Regulation of histone acetylation during memory formation in the hippocampus J. Biol. Chem. 279, 40545–40559.
Lonze, B.E., and Ginty, D.D. (2002).
Function and regulation of CREB family transcription factors in the nervous system. Neuron 35, 605–623.
Matijevic T, Knezevic J, Slavica M, Pavelic.(2009) RTT: from the gene to the disease.
McGee, A.W., Yang, Y., Fischer, Q.S., Daw, N.W., and Strittmatter, S.M. (2005). Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor. Science 309, 2222–2226.
McGill BE, Bundle SF, Yaylaoglu MB, Carson JP, Thaller C, Zoghbi HY. (2006) Enhanced anxiety and stress-induced corticosterone release are associated with increased Crh expression in a mouse model of Rett syndrome
Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18267-72
Meaney MJ (2001)
Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations.
Annu Rev Neurosci 24:1161-1192.
Meaney MJ, Szyf M.(2005)
Maternal care as a model for experience-dependent chromatin plasticity? Trends Neurosci. 2005 Sep;28(9):456-63
Moretti P, Levenson JM, Battaglia F, Atkinson R, Teague R, Antalffy B, Armstrong D, Arancio O, Sweatt JD, Zoghbi HY (2006)
Learning and memory and synaptic plasticity are impaired in a mouse model of RTT. J Neurosci 26:319-327.
Mower AF, Liao DS, Nestler EJ, Neve RL, Ramoa AS.(2002)
cAMP/Ca2+ response element-binding protein function is essential for ocular dominance plasticity.
J Neurosci. 2002 Mar 15;22(6):2237-45.
Nag N, Moriuchi JM, Peitzman CG, Ward BC, Kolodny NH, Berger-Sweeney JE (2009)
Environmental enrichment alters locomotor behaviour and ventricular volume in Mecp2 1lox mice.
Naka, F., Narita, N., Okado, N. & Narita, M. (2005)
Modification of AMPA receptor properties following environmental enrichment. Brain Dev. 27, 275–278 (2005).
Naruse Y, Oh-hashi K, Iijima N, Naruse M, Yoshioka H, Tanaka M.(2004)
Circadian and light-induced transcription of clock gene Per1 depends on histone acetylation and deacetylation.
Mol Cell Biol. 2004 Jul;24(14):6278-87.
Nithianantharajah J, Hannan AJ.(2006)
Enriched environments, experience-dependent plasticity and disorders of the nervous system.
Nat Rev Neurosci. 2006 Sep;7(9):697-709
Oitzl MS, Workel JO, Fluttert M, Frosch F, De Kloet ER (2000)
Maternal deprivation affects behaviour from youth to senescence: amplification of individual differences in spatial learning and memory in senescent Brown Norway rats. Eur J Neurosci 12:3771-3780.
Pelka GJ, Watson CM, Radziewic T, Hayward M, Lahooti H, Christodoulou J, Tam PP (2006)
Mecp2 deficiency is associated with learning and cognitive deficits and altered gene activity in the hippocampal region of mice.
Brain 129:887-898.
Pham, T.A., Impey, S., Storm, D.R., and Stryker, M.P. (1999).
CREmediated gene transcription in neocortical neuronal plasticity during the developmental critical period.
Neuron 22, 63–72.
Pizzorusso, T., Medini, P., Berardi, N., Chierzi, S., Fawcett, J.W., and Maffei, L. (2002).
Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298, 1248–1251.
Pizzorusso, T., Medini, P., Landi, S., Baldini, S., Berardi, N., and Maffei,L. (2006). Structural and functional recovery from early monocular deprivation in adult rats. Proc. Natl. Acad. Sci. USA 103, 8517–8522
Pizzorusso T, Berardi N, Maffei L.(2007) A richness that cures.
Neuron. 2007 May 24;54(4):508-10.
Prusky, G.T., West, P.W., and Douglas, R.M. (2000). Experiencedependent plasticity of visual acuity in rats. Eur. J. Neurosci. 12, 3781–3786.
Putignano E, Lonetti G, Cancedda L, Ratto G, Costa M, Maffei L, Pizzorusso T (2007).
Developmental downregulation of histone posttranslational modifications regulates visual cortical plasticity.
Neuron. 2007 Mar 1;53(5):747-59.
Reiss, A.L., Faruque, F., Naidu, S., Abrams, M., Beaty, T., Bryan, R.N., and Moser, H. (1993).
Neuroanatomy of RTT: a volumetric imaging study. Ann. Neurol. 34, 227–234.
Rosenzweig MR, Bennett EL, Hebert M, Morimoto H (1978)
Social grouping cannot account for cerebral effects of enriched environments. Brain Res 153:563-576.
Sale A, Putignano E, Cancedda L, Landi S, Cirulli F, Berardi N, Maffei L.(2004) Enriched environment and acceleration of visual system development.
Sawtell, N.B., Frenkel, M.Y., Philpot, B.D., Nakazawa, K., Tonegawa, S., and Bear, M.F. (2003).
NMDA receptor-dependent ocular dominance plasticity in adult visual cortex. Neuron 38, 977–985.
Schafe GE, Atkins CM, Swank MW, Bauer EP, Sweatt JD, LeDoux JE.(2000) Activation of ERK/MAP kinase in the amygdala is required for memory consolidation of Pavlovian fear conditioning.
J. Neurosci. 20, 8177–8187 (2000).
Shahbazian, M.D., Antalffy, B., Armstrong, D.L., and Zoghbi, H.Y. (2002b).
Insight into Rett syndrome: MeCP2 levels display tissue and cell-specific differences and correlate with neuronal maturation.
Hum. Mol. Genet. 11, 115–124.
Schmidt H, Kern W, Giese R, Hallschmid M, Enders A (2008)
Intranasal insulin to improve the developmental delay in children with 22q13 deletion syndrome: an exploratory clinical trial.
J Med Genet. Oct 23.
Selcher, J. C., Atkins, C. M., Trzaskos, J. M., Paylor, R. & Sweatt, J. D. (1999) A necessity for MAP kinase activation in mammalian spatial learning.
Learn. Mem. 6, 478–490 (1999).
Shahbazian M, Young J, Yuva-Paylor L, Spencer C, Antalffy B, Noebels J, Armstrong D, Paylor R, Zoghbi H (2002)
Mice with truncated MeCP2 recapitulate many RTT features and display hyperacetylation of histone H3.
Neuron 35:243-254.
Stearns NA, Schaevitz LR, Bowling H, Nag N, Berger UV, Berger-Sweeney J (2007)
Behavioral and anatomical abnormalities in Mecp2 mutant mice: a model for RTT. Neuroscience 146:907-921.
Suzuki, S., al-Noori, S., Butt, S.A., and Pham, T.A. (2004).
Regulation of the CREB signaling cascade in the visual cortex by visual experience and neuronal activity.
J. Comp. Neurol. 479, 70–83
Taha S, Hanover JL, Silva AJ, Stryker MP. (2002)
Autophosphorylation of aCaMKII is required for ocular dominance plasticity. Neuron 36, 483–491
Tao, X., Finkbeiner, S., Arnold, D.B., Shaywitz, A.J., and Greenberg, M.E. (1998). Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism.
Neuron 20, 709–726.
Thomas GM, Huganir RL. (2004)
MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci. 2004 Mar;5(3):173-83
van Dellen, A., Blakemore, C., Deacon, R., York, D., Hannan, A.J., 2000. Delaying the onset of Huntington's in mice.
Nature. 404, 721–722.
van Praag H, Kempermann G, Gage FH (2000) Neural consequences of environmental enrichment. Nat Rev Neurosci 1:191-198.
Vo N, Klein ME, Varlamova O, Keller DM, Yamamoto T, Goodman RH, Impey S. (2005)
A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis.
Weaver IC, Cervoni N, Champagne FA, D'Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ (2004)
Epigenetic programming by maternal behavior. Nat Neurosci 7:847-854.
Weeber EJ, Levenson JM, Sweatt JD.(2002) Molecular genetics of human cognition. Mol Interv. 2002 Oct;2(6):376-91, 339
Wigram T, Lawrence M.
Music therapy as a tool for assessing hand use and communicativeness in children with Rett Syndrome.
Brain Dev. 2005 Nov;27 Suppl 1:S95-S96
Wolfer DP, Crusio WE, Lipp HP (2002)
Knockout mice: simple solutions to the problems of genetic background and flanking genes.
Trends Neurosci 25:336-340.
Wood, M.A., Hawk, J.D., and Abel, T. (2006).
Combinatorial chromatin modifications and memory storage: a code for memory? Learn. Mem. 13, 241–244.
Zappella, M., Meloni, I., Longo, I., Hayek, G., and Renieri, A. (2001). Preserved speech variants of the RTT: molecular and clinical analysis. Am. J. Med. Genet. 104, 14–22.
Zhou, Z., Hong, E.J., Cohen, S., Zhao, W.N., Ho, H.Y., Schmidt, L., Chen, W.G., Lin, Y., Savner, E., Griffith, E.C., et al. (2006).
Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation.
Zoghbi HY (2003)
Postnatal neurodevelopmental disorders: meeting at the synapse? Science 302:826-830.
