Fragile X Syndrome is the most common form of inherited mental retardation worldwide. A Fragile X mouse model, fmr1(tm1Cgr), with a disruption in the X-linked Fmr1 gene, has three substantial deficits observed in several strains: (1) sensitivity to audiogenic seizures (AGS), (2) tendency to spend significantly more time in the center of an open field, and (3) enlarged testes. Alterations in metabotropic glutamate receptor group I signaling were previously identified in the fmr1(tm1Cgr) mouse. In this study, we examined the effect of MPEP, an antagonist of the group I metabotropic glutamate receptor mGluR5, on audiogenic seizures and open field activity of fmr1(tm1Cgr) mice. Genetic analysis revealed synergistic reactions between fmr1(tm1Cgr) and inbred AGS alleles. In addition, AGS sensitivity due to the fmr1(tm1Cgr) allele was restricted during development. Examination of phenotypes combining mGluR5 inhibition and Fmr1 mutation indicated that absence of FMRP may affect mGluR5 signaling through indirect as well as direct pathways. All strains of fmr1(tm1Cgr) mice tested (FVB/NJ, C57BL/6J, and an F1 hybrid of the two) had a more excitable AGS pathway than wild-type, and consequently required more MPEP to achieve seizure suppression. At high doses of mGluR5 antagonists, a Fragile X specific tolerance (loss of drug activity) was observed. The tolerance effect could be overcome by a further increase in drug dose. In open field tests, MPEP reduced fmr1(tm1Cgr) center field behavior to one indistinguishable from wild-type. Therefore, mGluR5 antagonists were able to rescue two of the major phenotypes of the FX mouse. Modulation of mGluR5 signaling may allow amelioration of symptoms of Fragile X Syndrome.

Fragile X Syndrome is the most common form of inherited mental retardation. It is also known for having a substantial behavioral morbidity, including autistic features. In humans, Fragile X Syndrome is almost always caused by inactivation of the X-linked FMR1 gene. A single knockout mouse model, fmr1-tm1Cgr, exists. In this report we further characterize the cognitive and behavioral phenotype of the fmr1-tm1Cgr Fragile X mouse through the use of F1 hybrid mice derived from two inbred strains (FVB/NJ and C57BL/6J). Use of F1 hybrids allows focus on the effects of the fmr1-tm1Cgr allele with reduced influence from recessive alleles present in the parental inbred strains. We find that the cognitive phenotype of fmr1-tm1Cgr mice, including measures of working memory and learning set formation that are known to be seriously impacted in humans with Fragile X Syndrome, are essentially normal. Further testing of inbred strains supports this conclusion. Thus, any fmr1-tm1Cgr cognitive deficit is surprisingly mild or absent. There is, however, clear support presented for a robust audiogenic seizure phenotype in all strains tested, as well as increased entries into the center of an open field. Finally, a molecular examination of the fmr1-tm1Cgr mouse shows that, contrary to common belief, it is not a molecular null. Implications of this finding for interpretation of the phenotype are discussed.

a b s t r a c tSignificant advances have been made in understanding the underlying defects of and developing potential treatments for Fragile X syndrome (FXS), the most common heritable mental retardation. It has been shown that neuronal metabotropic glutamate receptor 5 (mGluR5)-mediated signaling is affected in FX animal models, with consequent alterations in activity-dependent protein translation and synaptic spine functionality. We demonstrate here that a central metabolic regulatory enzyme, glycogen synthase kinase-3 (GSK3) is present in a form indicating elevated activity in several regions of the FX mouse brain. Furthermore, we show that selective GSK3 inhibitors, as well as lithium, are able to revert mutant phenotypes of the FX mouse. Lithium, in particular, remained effective with chronic administration, although its effects were reversible even when given from birth. The combination of an mGluR5 antagonist and GSK3 inhibitors was not additive. Instead, it was discovered that mGluR5 signaling and GSK3 activation in the FX mouse are coordinately elevated, with inhibition of mGluR5 leading to inhibition of GSK3. These findings raise the possibility that GSK3 is a fundamental and central component of FXS pathology, with a substantial treatment potential.

Mutations in FMR1, which encodes the fragile X mental retardation protein (FMRP), are the cause of fragile X syndrome (FXS), an X-linked mental retardation disorder. Inactivation of the mouse gene Fmr1 confers a number of FXS-like phenotypes including an enhanced susceptibility to epileptogenesis during development. We find that in a FXS mouse model, in which the function of FMRP is suppressed, synaptically released glutamate induced prolonged epileptiform discharges resulting from enhanced group I metabotropic glutamate receptor (mGluR)-mediated responses in hippocampal slices. The induction of the group I mGluR-mediated, prolonged epileptiform discharges was inhibited in preparations that were pretreated with inhibitors of ERK1/2 (extracellular signal-regulated kinase 1/2) phosphorylation or of mRNA translation, and their maintenance was suppressed by group I mGluR antagonists. The results suggest that FMRP plays a key role in the control of signaling at the recurrent glutamatergic synapses in the hippocampus. The absence of this control causes the synaptically activated group I mGluRs to elicit translation-dependent epileptogenic activities.

Neural stem cells (NSCs) are important pluripotent stem cells, which have potential applications in cell replacement therapy. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) have been demonstrated to exert a marked impact on the proliferation and differentiation of NSCs. The effects of NGF, BDNF, and BDNF combined with NGF on NSC neuronal differentiation and the possible mechanisms for these effects were investigated in this study. An adherent monolayer culture was employed to obtain highly homogeneous NSCs. The cells were divided into four groups: Control, NGF, BDNF and combination (BDNF + NGF) groups. Neuron differentiation was examined using immunocytochemistry and phospho-extracellular signal-regulated kinase (p-ERK) levels were analyzed using western blotting. Reverse transcription polymerase chain reaction was used to measure the mRNA expression levels of the HES1, HES5, MASH1, NGN1 and NeuroD transcription factors at different time intervals following neurotrophin-induced differentiation. NGF and BDNF were observed to induce NSC neuronal differentiation, and β-tubulin III-positive cells and p-ERK expression levels were highest in the NGF + BDNF combination group at all time points. The proportion of β-tubulin III-positive neurons in each group was associated with the expression levels of MASH1, NGN1 and NeuroD in the group. In conclusion, BDNF combined with NGF significantly improved NSC neuronal differentiation, which may provide support for the practical application of NSCs in neurodegenerative diseases.

BackgroundMultiple sclerosis is a chronic demyelinating disease of uncertain etiology. Traditional treatment methods produce more adverse effects. Epidemiological and clinical treatment findings showed that unknown environmental factors contribute to the etiology of MS and that diet is a commonly assumed factor. Despite the huge interest in diet expressed by people with MS and the potential role diet plays in MS, very little data is available on the role of diet in MS pathogenesis and MS course, in particular, studies on fats and MS. The oil of Acer truncatum is potential as a resource to be exploited in the treatment of some neurodegenerative diseases.ObjectiveHere, we investigated the underlying influences of Acer truncatum oil on the stimulation of remyelination in a cuprizone mouse model of demyelination.MethodsCuprizone (0.2% in chow) was used to establish a mouse model of demyelination. Acer truncatum oil was administrated to mice during remyelination. Following techniques were used: behavioral test, histochemistry, fluorescent immunohistochemistry, transmission electron microscope.ResultsMice exposed to cuprizone for 6 weeks showed schizophrenia-like behavioral changes, the increased exploration of the center in the open field test (OFT), increased entries into the open arms of the elevated plus-maze, as well as demyelination in the corpus callosum. After cuprizone withdrawal, the diet therapy was initiated with supplementation of Acer truncatum oil for 2 weeks. As expected, myelin repair was greatly enhanced in the demyelinated regions with increased mature oligodendrocytes (CC1) and myelin basic protein (MBP). More importantly, the supplementation with Acer truncatum oil in the diet reduced the schizophrenia-like behavior in the open field test (OFT) and the elevated plus-maze compared to the cuprizone recovery group. The results revealed that the diet supplementation with Acer truncatum oil improved behavioral abnormalities, oligodendrocyte maturation, and remyelination in the cuprizone model during recovery.ConclusionDiet supplementation with Acer truncatum oil attenuates demyelination induced by cuprizone, indicating that Acer truncatum oil is a novel therapeutic diet in demyelinating diseases.

We first established the PND procedure with pathogenicity assessment in FXIIID patients. The F13A gene mutations' spectrum of the Chinese Han population was enriched.

The established genetic diagnosis strategy for HB in our study was comprehensive and well applied in clinic practice. Besides, we recommended that DNA direct sequencing combined with Karyomapping was a better PGD protocol.