Fragile X Syndrome Patients Research Articles

Cell-Type Specific Channelopathies in the Prefrontal Cortex of the fmr1-/y Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is caused by transcriptional silencing of the fmr1 gene resulting in the loss of fragile X mental retardation protein (FMRP) expression. FXS patients display several behavioral phenotypes associated with prefrontal cortex (PFC) dysfunction. Voltage-gated ion channels, some of which are regulated by FMRP, heavily influence PFC neuron function. Although there is evidence for brain region-specific alterations to the function a single type of ion channel in FXS, it is unclear whether subtypes of principal neurons within a brain region are affected uniformly. We tested for alterations to ion channels critical in regulating neural excitability in two subtypes of prefrontal L5 pyramidal neurons. Using somatic and dendritic patch-clamp recordings, we provide evidence that the functional expression of h-channels (Ih) is down-regulated, whereas A-type K+ channel function is up-regulated in pyramidal tract-projecting (PT) neurons in the fmr1-/y mouse PFC. This is the opposite pattern of results from published findings from hippocampus where Ih is up-regulated and A-type K+ channel function is down-regulated. Additionally, we find that somatic Kv1-mediated current is down-regulated, resulting in increased excitability of fmr1-/y PT neurons. Importantly, these h- and K+ channel differences do not extend to neighboring intratelencephalic-projecting neurons. Thus, the absence of FMRP has divergent effects on the function of individual types of ion channels not only between brain regions, but also variable effects across cell types within the same brain region. Given the importance of ion channels in regulating neural circuits, these results suggest cell-type-specific phenotypes for the disease.

Reversion of FMR1 Methylation and Silencing by Editing the Triplet Repeats in Fragile X iPSC-Derived Neurons.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability, resulting from a CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. Here, we report a strategy for CGG repeat correction using CRISPR/Cas9 for targeted deletion in both embryonic stem cells and induced pluripotent stem cells derived from FXS patients. Following gene correction in FXS induced pluripotent stem cells, FMR1 expression was restored and sustained in neural precursor cells and mature neurons. Strikingly, after removal of the CGG repeats, the upstream CpG island of the FMR1 promoter showed extensive demethylation, an open chromatin state, and transcription initiation. These results suggest a silencing maintenance mechanism for the FMR1 promoter that is dependent on the existence of the CGG repeat expansion. Our strategy for deletion of trinucleotide repeats provides further insights into the molecular mechanisms of FXS and future therapies of trinucleotide repeat disorders.

Patient and Caregiver Burden Associated With Fragile X Syndrome in the United States.

This study evaluated the incremental healthcare costs associated with Fragile X syndrome (FXS) for patients and their caregivers. Using administrative healthcare claims data (1999-2012), subjects with ≥ 1 FXS diagnosis (ICD-9-CM: 759.83) were matched 1:5 with non-FXS controls using high-dimensional propensity scores. Costs and resource utilization were examined. Among employees, payment for disability leave and absenteeism were also examined. We identified 590 FXS and 2,950 non-FXS individuals along with 647 and 2,611 caregivers, respectively. FXS patients and their caregivers experienced higher all-cause direct costs compared to control cohorts (total[SD]: $14,677[46,752] vs. $6,103[26,081]; $5,259[19,360] vs. $2,120[6,425], respectively, p < 0.05). Employed FXS patients and caregivers had higher indirect costs compared to their controls (total[SD]: $4,477[5,161] vs. $1,751[2,556]; $2,641[4,238] vs. $1,211[1,936], respectively, p < 0.05).

NNZ-2566, a novel analog of (1-3) IGF-1, as a potential therapeutic agent for fragile X syndrome.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, and many agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. In the present work, a novel pharmacological approach for FXS is investigated. NNZ-2566, a synthetic analog of a naturally occurring neurotrophic peptide derived from insulin-like growth factor-1 (IGF-1), was administered to fmr1 knockout mice correcting learning and memory deficits, abnormal hyperactivity and social interaction, normalizing aberrant dendritic spine density, overactive ERK and Akt signaling, and macroorchidism. Altogether, our results indicate a unique disease-modifying potential for NNZ-2566 in FXS. Most importantly, the present data implicate the IGF-1 molecular pathway in the pathogenesis of FXS. A clinical trial is under way to ascertain whether these findings translate into clinical effects in FXS patients.

PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.

Fragile X syndrome as a rare disease in China - Therapeutic challenges and opportunities.

Recognized as the most common inherited from of intellectual disability (ID) and the most common known monogenic cause of autism spectrum disorders (ASD), Fragile X syndrome (FXS) is identified as an unmet medical need for the development of personalized medicine and targeted therapeutics for neurodevelopment disorders as a result of improved understanding of the genetic and cellular mechanisms. Consequently promising pharmacological targets have emerged from basic and translational research, are now being pursued by global pharmaceutical and biotech companies in early proof-of-concept clinical trials. With the world's largest rare disease population, China potentially has a large number of FXS patients, many of whom are under-diagnosed or even misdiagnosed, barely with any treatment. In spite of improved awareness of FXS in recent years, big gaps still exist between China and developed countries in multiple aspects. With increased public awareness, strong government support and investment, coupled with an increasingly large number of Western-trained experienced researchers engaging in new drug discovery and development, China has the potential to become an important player in the discovery of effective diagnostics and treatments for a rare disease like FXS.

Anti-Neuronal Antibodies in Patients with Fragile X Syndrome: Is there a Role of Autoimmunity in Its Pathogenesis?

Background: Fragile X syndrome (FXS) is a single-gene disorder with a broad spectrum of involvement, including cognitive and behavioural impairments of varying degrees with specific physical features and a strong association with autism. Objectives: In this study, the frequency of serum anti-neural antibodies was investigated in FXS patients who did and those who did not manifest autism spectrum disorders (ASD) in comparison to typically developing controls. Methods: The study involved 23 males (mean age, 19.78 ± 6.56 years) who harboured a full mutation in the FMR1 gene. The control group comprised 19 healthy students (mean age 24.63 ± 1.89 years). Serum anti-neuronal antibodies were analyzed using Western blotting. Results: Serum anti-neuronal antibodies were present in 10/23 (43.48%) FXS males. Conclusion: Serum anti-neuronal antibodies were found in a subgroup of FXS patients. Autistic symptoms in FXS may, in part, be caused by auto-immune factors. Further studies in larger patient and control groups are necessary to elucidate the aetiopathogenic role of anti-neuronal antibodies in FXS patients.

Identification of fragile X syndrome specific molecular markers in human fibroblasts: a useful model to test the efficacy of therapeutic drugs.

Fragile X syndrome (FXS) is the most frequent cause of inherited intellectual disability and autism. It is caused by the absence of the fragile X mental retardation 1 (FMR1) gene product, fragile X mental retardation protein (FMRP), an RNA-binding protein involved in the regulation of translation of a subset of brain mRNAs. In Fmr1 knockout mice, the absence of FMRP results in elevated protein synthesis in the brain as well as increased signaling of many translational regulators. Whether protein synthesis is also dysregulated in FXS patients is not firmly established. Here, we demonstrate that fibroblasts from FXS patients have significantly elevated rates of basal protein synthesis along with increased levels of phosphorylated mechanistic target of rapamycin (p-mTOR), phosphorylated extracellular signal regulated kinase 1/2, and phosphorylated p70 ribosomal S6 kinase 1 (p-S6K1). The treatment with small molecules that inhibit S6K1 and a known FMRP target, phosphoinositide 3-kinase (PI3K) catalytic subunit p110β, lowered the rates of protein synthesis in both control and patient fibroblasts. Our data thus demonstrate that fibroblasts from FXS patients may be a useful in vitro model to test the efficacy and toxicity of potential therapeutics prior to clinical trials, as well as for drug screening and designing personalized treatment approaches.

35.: Case report: Concurrent occurrence of Fragile X syndrome and Fragile X associated tremor ataxia syndrome due to CGG repeat and methylation mosaicism

Fragile X syndrome (FXS) is a genetic disorder resulting from CGG trinucleotide repeat lengths greater than 200 and subsequent methylation of the FMR1 gene on the X chromosome. Fragile X associated tremor/ataxia syndrome (FXTAS) is a recently described syndrome of tremor and ataxia in a relative of a FXS patient with clinical signs not seen in typical FXS patients. This syndrome is typically seen in patients over the age of 50 and is thought to be a result of neuronal toxicity from excess mRNA production due to CGG repeat lengths of 55 to 200. We present a 34-year-old gentleman with a previous diagnosis of FXS presenting with phenotypic features of FXTAS including cerebellar ataxia. Genetic testing with methylation assay revealed that he is a FXS and FXTAS mosaic with methylated CGG repeat lengths of 110 and 540 contributing to FXS and unmethylated CGG repeat lengths of 90 and 600 contributing to cerebellar ataxia and diagnosis of FXTAS. Despite the close genotypic relationship between FXS an FXTAS there are distinct phenotypic differences attributable to different methylation state. To our knowledge this is the first case to be reported of FXS/FXTAS mosaicism and adds to the increasing understanding of the role played by methylation in determining phenotypic expression of genetic disorders, in particular the importance of methylation mosaicism. We suggest that in a FXS patient presenting with cerebellar ataxia or tremor without an apparent cause, further genetic testing with methylation analysis should be considered in the diagnostic process.

Lithium: a promising treatment for fragile X syndrome.

Fragile X syndrome (FXS) is an inherited disorder that results in intellectual disability and a characteristic behavioral profile that includes autism spectrum disorder, attention deficit hyperactivity disorder, sensory hypersensitivity, hyperarousal, and anxiety. The epigenetic silencing of FMR1 and the consequent absence of its protein product, FMRP, is the most common cause of fragile X. The development of animal models of fragile X syndrome 20 years ago has produced a considerable increase in our understanding of the consequences of the absence of FMRP on the structure and function of the nervous system. Some of the insights gained have led to proposals of treatment strategies that are based on cellular and molecular changes observed in animals lacking FMRP. One such proposal is treatment with lithium, a drug with a long history of clinical efficacy in psychiatry and a drug with newly described uses in degenerative disorders of the nervous system. Lithium treatment has been studied extensively in both mouse and fruit fly models of FXS, and it has been shown to reverse numerous behavioral, physiological, cellular, and molecular phenotypes. A report of a pilot clinical trial on a limited number of adult FXS patients indicated that measurable improvements in behavior and function were seen after 2 months of lithium treatment. A double-blind clinical trial of lithium treatment in FXS patients is now needed.

Anxiety, hyperactivity and stereotypy in a zebrafish model of fragile X syndrome and autism spectrum disorder

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and is caused by a loss of function of the fragile X mental retardation (fmr1) gene. Animal fmr1-knockout (KO) models are not only of interest for the study of FXS, but have also important implications for our understanding of autism spectrum disorder (ASD). Here we report the behavioral changes in fmr1-knockout zebrafish in an open field with two white and two transparent walls. The neophobic responses that in wild-type (WT) zebrafish normally occur during the first 5-10 min in an unfamiliar environment (such as freezing, hypo-activity and preferences for the bottom and opaque walls of the tank), were weakened in fmr1 mutants, suggesting a reduction of novelty-induced anxiety. The fmr1-KO zebrafish showed somewhat increased vertical activity beyond the 'neophobic phase', but no overall hyperactivity. The mutants demonstrated a clear habituation-independent preference for the transparent walls. Whether this was attributable to altered spatial information processing or to reduced avoidance of open spaces is discussed. Finally, since restrictive repetitive (or stereotypical) behaviors are frequently present in FXS and ASD patients, we analyzed relative turning angles, directional and preferential turning ratios and performed frequency-domain analysis. However, no indications of abnormal movement patterning were detected. The possible reasons for the absence of stereotypical behaviors are discussed in terms of behavioral endpoint selection and of eliciting conditions. Overall, our findings are consistent with those reported in fmr1-KO mice and suggest that further analysis of the fmr1-KO zebrafish model has potential to deepen our understanding of FXS and ASD.

Impaired sensorimotor gating in Fmr1 knock out and Fragile X premutation model mice

Fragile X syndrome (FXS) is a common inherited cause of intellectual disability that results from a CGG repeat expansion in the FMR1 gene. Large repeat expansions trigger both transcriptional and translational suppression of Fragile X protein (FMRP) production. Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is an allelic neurodegenerative disease caused by smaller "pre-mutation" CGG repeat expansions that enhance FMR1 transcription but lead to translational inefficiency and reduced FMRP expression in animal models. Sensorimotor gating as measured by pre-pulse inhibition (PPI) is altered in both FXS patients and Fmr1 knock out (KO) mice. Similarly, FXTAS patients have demonstrated PPI deficits. Recent work suggests there may be overlapping synaptic defects between Fmr1 KO and CGG knock-in premutation mouse models (CGG KI). We therefore sought to interrogate PPI in CGG KI mice. Using a quiet PPI protocol more akin to human testing conditions, we find that Fmr1 KO animals have significantly impaired PPI. Using this same protocol, we find CGG KI mice demonstrate an age-dependent impairment in PPI compared to wild type (WT) controls. This study describes a novel phenotype in CGG KI mice that can be used in future therapeutic development targeting premutation associated symptoms.

Auditory Processing in Fragile X Syndrome

Fragile X syndrome (FXS) is an inherited form of intellectual disability and autism. Among other symptoms, FXS patients demonstrate abnormalities in sensory processing and communication. Clinical, behavioral, and electrophysiological studies consistently show auditory hypersensitivity in humans with FXS. Consistent with observations in humans, the Fmr1 KO mouse model of FXS also shows evidence of altered auditory processing and communication deficiencies. A well-known and commonly used phenotype in pre-clinical studies of FXS is audiogenic seizures. In addition, increased acoustic startle response is seen in the Fmr1 KO mice. In vivo electrophysiological recordings indicate hyper-excitable responses, broader frequency tuning, and abnormal spectrotemporal processing in primary auditory cortex of Fmr1 KO mice. Thus, auditory hyper-excitability is a robust, reliable, and translatable biomarker in Fmr1 KO mice. Abnormal auditory evoked responses have been used as outcome measures to test therapeutics in FXS patients. Given that similarly abnormal responses are present in Fmr1 KO mice suggests that cellular mechanisms can be addressed. Sensory cortical deficits are relatively more tractable from a mechanistic perspective than more complex social behaviors that are typically studied in autism and FXS. The focus of this review is to bring together clinical, functional, and structural studies in humans with electrophysiological and behavioral studies in mice to make the case that auditory hypersensitivity provides a unique opportunity to integrate molecular, cellular, circuit level studies with behavioral outcomes in the search for therapeutics for FXS and other autism spectrum disorders.

Neurochemical evaluation of brain function with 1H magnetic resonance spectroscopy in patients with fragile X syndrome

Fragile X syndrome (FXS) is the most common hereditary disorder of intellectual disability. Cognitive deficits involve executive function, attention, learning and memory. Advanced neuroimaging techniques are available, and (1)H magnetic resonance spectroscopy (MRS) can be used as a complementary method to MR imaging to understand disease processes in brain, by in vivo demonstration of brain metabolites. MRS was performed in 13 male patients with FXS full mutation, and 13 age- and sex-matched healthy controls. FXS diagnosis was based on clinical evaluation, followed by detection of FMR1 full mutation. Axial T2 TSE, sagittal T1 SE and coronal 3D MPRAGE images were obtained for both morphological imaging and voxel localization. Following evaluation of conventional images, multivoxel MRS (CSI) through supraventricular white matter and single voxel MRS (svs) with an intermediate echo time (TE:135 ms) from the cerebellar vermis were performed. Choline/Creatine (Cho/Cr), N-acetyl aspartate/Creatine (NAA/Cr), and Choline/N-acetyl aspartate (Cho/NAA) ratios were examined at right frontal (RF), left frontal (LF), right parietal (RP), left parietal (LP), and cerebellar vermian (C) white matter. Statistical analyses were done using t-test and Mann-Whitney U tests. A statistically significant difference was observed in RP Cho/NAA ratio (cell membrane marker/neuroaxonal marker), FXS patients having lower levels than controls (P = 0.016). The results should be evaluated cautiously in parallel to consequences in brain metabolism leading to alterations in neurotransmitter levels, osmoregulation, energy metabolism and oxidative stress response described in animal models. MRS may serve to define a metabolic signature and biomarkers associated with FXS.

Syntax at Hand: Common Syntactic Structures for Actions and Language

Evidence that the motor and the linguistic systems share common syntactic representations would open new perspectives on language evolution. Here, crossing disciplinary boundaries, we explore potential parallels between the structure of simple actions and that of sentences. First, examining Typically Developing (TD) children displacing a bottle with or without knowledge of its weight prior to movement onset, we provide kinematic evidence that the sub-phases of this displacing action (reaching + moving the bottle) manifest a structure akin to linguistic embedded dependencies. Then, using the same motor task, we reveal that children suffering from specific language impairment (SLI), whose core deficit affects syntactic embedding and dependencies, manifest specific structural motor anomalies parallel to their linguistic deficits. In contrast to TD children, SLI children performed the displacing-action as if its sub-phases were juxtaposed rather than embedded. The specificity of SLI’s structural motor deficit was confirmed by testing an additional control group: Fragile-X Syndrome patients, whose language capacity, though delayed, comparatively spares embedded dependencies, displayed slower but structurally normal motor performances. By identifying the presence of structural representations and dependency computations in the motor system and by showing their selective deficit in SLI patients, these findings point to a potential motor origin for language syntax.

Increasing our understanding of human cognition through the study of fragile X syndrome

Fragile X Syndrome (FXS) is considered the most common form of inherited intellectual disability. It is caused by reductions in the expression level or function of a single protein, the Fragile X Mental Retardation Protein (FMRP), a translational regulator which binds to approximately 4% of brain messenger RNAs. Accumulating evidence suggests that FXS is a complex disorder of cognition, involving interactions between genetic and environmental influences, leading to difficulties in acquiring key life skills including motor skills, language, and proper social behaviors. Since many FXS patients also present with one or more features of autism spectrum disorders (ASDs), insights gained from studying the monogenic basis of FXS could pave the way to a greater understanding of underlying features of multigenic ASDs. Here we present an overview of the FXS and FMRP field with the goal of demonstrating how loss of a single protein involved in translational control affects multiple stages of brain development and leads to debilitating consequences on human cognition. We also focus on studies which have rescued or improved FXS symptoms in mice using genetic or therapeutic approaches to reduce protein expression. We end with a brief description of how deficits in translational control are implicated in FXS and certain cases of ASDs, with many recent studies demonstrating that ASDs are likely caused by increases or decreases in the levels of certain key synaptic proteins. The study of FXS and its underlying single genetic cause offers an invaluable opportunity to study how a single gene influences brain development and behavior. © 2013 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 74: 147–177, 2014

A Delicate Balance in Fragile X

Biomedicine Endocannabinoids are lipids that modulate cognition, anxiety, mood, and pain sensation—all behaviors that are deficient in patients with fragile X syndrome (FXS). FXS is a genetic disorder in which fragile X mental retardation protein (FMRP), an RNA-binding protein that controls protein synthesis, is not expressed in neurons. Treatments for the condition are focused on alleviating the symptoms. Busquets-Garcia et al. suggest that targeting the endocannabinoid system could be a new therapeutic approach for FXS. When rimonabant, a drug that blocks endocannabinoid receptor CB1R, was injected into the hippocampus of FMRP-deficient mice (a good model for FXS), the animals showed improved memory and sensitivity to pain. In pyramidal neurons, activation of the receptor mGluR5 by excitatory glutaminergic neurons triggers the mTor signaling pathway to control gene expression and synaptic plasticity. Activation of this pathway is elevated in FXS, and rimonabant normalized the phosphorylation of pathway components Akt and p70S6K in the FXS mouse model. Genetic deletion of CB1R blunted the therapeutic effects of the drug. Furthermore, an antagonist of the CB2R endocannabinoid receptor specifically normalized anxiety-like behavior in the FXS mouse model. These observations suggest that modulating endocannabinoids in FXS patients could improve cognitive abilities and anxiety, among other symptoms. Nat. Med. 19 , 10.1038/nm.3127 (2013).

Is metabotropic glutamate receptor 5 upregulated in prefrontal cortex in fragile X syndrome?

BackgroundFragile X syndrome (FXS) is a common inherited form of intellectual disability caused by loss of function of the fragile X mental retardation protein. Recent animal studies suggest that upregulated downstream signaling by metabotropic glutamate receptor 5 (mGluR5) might be an important mechanism for cognitive and behavioral abnormalities associated with FXS. However, mGluR5 density in human FXS remains unknown.MethodsReceptor binding and protein expression were measured in the postmortem prefrontal cortex of 14 FXS patients or carriers and 17 age- and sex-matched control subjects without neurological disorders. In-vitro binding assays were performed using [3H]-labeled 3-methoxy-5-pyridin-2-ylethynylpyridine (MPEPy), a selective and high-affinity negative allosteric modulator of mGluR5, to measure receptor density and the radioligand’s dissociation constant, which is inversely proportional to affinity. Immunoblotting was also performed, to measure mGluR5 protein expression.ResultsThe mGluR5 density increased with marginal significance (+16%; P = 0.058) in the prefrontal cortex of FXS patients or carriers compared with matched healthy controls. No significant change in dissociation constant (-4%; P = 0.293) was observed. Immunoblotting found a significant elevation (+32%; P = 0.048) in mGluR5 protein expression.ConclusionsBoth mGluR5 binding density and protein expression were increased in the brains of FXS patients or carriers, but only expression was significantly different, which could be because of the small sample size and moderate variability. Another important caveat is that the effects of psychotropic medications on mGluR5 expression are largely unknown. Future in-vivo measurement of mGluR5 with positron emission tomography might characterize the role of this receptor in the pathophysiology of FXS and facilitate trials of mGluR5-oriented treatments for this disorder.

Fragile X Syndrome in China

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID), and the leading monogenic cause of autism spectrum disorders. The FXS cases in China were first reported in 1984, and effort has been made to improve the wellbeing of FXS patients. However, the general Chinese population is unfamiliar with FXS due to the limited public education. Even among those with medical training, there is a lack of awareness. Here our review aims to provide basic information on FXS, introduce the clinical aspects of FXS in China, and outline future research and policy recommendations that may in the future improve FXS genetic testing and counselor training in the Chinese health system. [N A J Med Sci. 2013;6(4):181-185. DOI: 10.7156/najms.2013.0604181]

Longitudinal in vivo developmental changes of metabolites in the hippocampus of Fmr1 knockout mice

Fragile X syndrome (FXS) is the most common form of inherited mental retardation and is studied in the Fmr1 knockout (KO) mouse, which models both the anatomical and behavioral changes observed in FXS patients. In vitro studies have shown many alterations in synaptic plasticity and increased density of immature dendritic spines in the hippocampus, a region involved in learning and memory. In this study, magnetic resonance imaging (MRI) and (1) H magnetic resonance spectroscopy (MRS) were used to determine in vivo longitudinal changes in volume and metabolites in the hippocampus during the critical period of early myelination and synaptogenesis at post-natal days (PND) 18, 21, and 30 in Fmr1 KO mice compared with wild-type (WT) controls. MRI demonstrated an increase in volume of the hippocampus in the Fmr1 KO mouse compared with controls. MRS revealed significant developmental changes in the ratios of hippocampal metabolites N-acetylaspartate (NAA), myo-inositol (Ins), and taurine to total creatine (tCr) in Fmr1 KO mice compared with WT controls. Ins was decreased at PND 30, and taurine was increased at all ages studied in Fmr1 KO mice compared with controls. An imbalance of brain metabolites in the hippocampus of Fmr1 KO mice during the critical developmental period of synaptogenesis and early myelination could have long-lasting effects that adversely affect brain development and contribute to ongoing alterations in brain function.