Pathophysiology Of Fragile X Syndrome Research Articles

Activation of the 5-HT1A Receptor by Eltoprazine Restores Mitochondrial and Motor Deficits in a Drosophila Model of Fragile X Syndrome.

Neurons rely on mitochondrial energy metabolism for essential functions like neurogenesis, neurotransmission, and synaptic plasticity. Mitochondrial dysfunctions are associated with neurodevelopmental disorders including Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, which also presents with motor skill deficits. However, the precise role of mitochondria in the pathophysiology of FXS remains largely unknown. Notably, previous studies have linked the serotonergic system and mitochondrial activity to FXS. Our study investigates the potential therapeutic role of serotonin receptor 1A (5-HT1A) in FXS. Using the Drosophila model of FXS, we demonstrated that treatment with eltoprazine, a 5-HT1A agonist, can ameliorate synaptic transmission, correct mitochondrial deficits, and ultimately improve motor behavior. While these findings suggest that the 5-HT1A-mitochondrial axis may be a promising therapeutic target, further investigation is needed in the context of FXS.

Cell- and Pathway-Specific Disruptions in the Accumbens of Fragile X Mouse.

Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism spectrum disorder. The mesocorticolimbic system, which includes the prefrontal cortex (PFC), basolateral amygdala (BLA), and nucleus accumbens core (NAcC), is essential for regulating socioemotional behaviors. We employed optogenetics to compare the functional properties of the BLA→NAcC, PFC→NAcC, and reciprocal PFC↔BLA pathways in Fmr1-/y::Drd1a-tdTomato male mice. In FXS mice, the PFC↔BLA reciprocal pathway was unaffected, while significant synaptic modifications occurred in the BLA/PFC→NAcC pathways. We observed distinct changes in D1 striatal projection neurons (SPNs) and separate modifications in D2 SPNs. In FXS mice, the BLA/PFC→NAcC-D2 SPN pathways demonstrated heightened synaptic strength. Focusing on the BLA→NAcC pathway, linked to autistic symptoms, we found increased AMPAR and NMDAR currents and elevated spine density in D2 SPNs. Conversely, the amplified firing probability of BLA→NAcC-D1 SPNs was not accompanied by increased synaptic strength, AMPAR and NMDAR currents, or spine density. These pathway-specific alterations resulted in an overall enhancement of excitatory-to-spike coupling, a physiologically relevant index of how efficiently excitatory inputs drive neuronal firing, in both BLA→NAcC-D1 and BLA→NAcC-D2 pathways. Finally, the absence of fragile X messenger ribonucleoprotein 1 (FMRP) led to impaired long-term depression specifically in BLA→D1 SPNs. These distinct alterations in synaptic transmission and plasticity within circuits targeting the NAcC highlight the potential role of postsynaptic mechanisms in selected SPNs in the observed circuit-level changes. This research underscores the heightened vulnerability of the NAcC in the context of FMRP deficiency, emphasizing its pivotal role in the pathophysiology of FXS.

Implication of the endocannabidiome and metabolic pathways in fragile X syndrome pathophysiology

Fragile X Syndrome (FXS) results from the silencing of the FMR1 gene and is the most prevalent inherited cause of intellectual disability and the most frequent monogenic cause of autism spectrum disorder. It is well established that Fragile X individuals are subjected to a wide array of comorbidities, ranging from cognitive, behavioural, and medical origin. Furthermore, recent studies have also described metabolic impairments in FXS individuals. However, the molecular mechanisms linking FMRP deficiency to improper metabolism are still misunderstood. The endocannabinoidome (eCBome) is a lipid-based signalling system that regulates several functions across the body, ranging from cognition, behaviour and metabolism. Alterations in the eCBome have been described in FXS animal models and linked to neuronal hyperexcitability, a core deficit of the disease. However, the potential link between dysregulation of the eCBome and altered metabolism observed in FXS remains unexplored. As such, this review aims to overcome this issue by describing the most recent finding related to eCBome and metabolic dysfunctions in the context of FXS. A better comprehension of this association will help deepen our understanding of FXS pathophysiology and pave the way for future therapeutic interventions.

Astroglial Kir4.1 potassium channel deficit drives neuronal hyperexcitability and behavioral defects in Fragile X syndrome mouse model

Fragile X syndrome (FXS) is an inherited form of intellectual disability caused by the loss of the mRNA-binding fragile X mental retardation protein (FMRP). FXS is characterized by neuronal hyperexcitability and behavioral defects, however the mechanisms underlying these critical dysfunctions remain unclear. Here, using male Fmr1 knockout mouse model of FXS, we identify abnormal extracellular potassium homeostasis, along with impaired potassium channel Kir4.1 expression and function in astrocytes. Further, we reveal that Kir4.1 mRNA is a binding target of FMRP. Finally, we show that the deficit in astroglial Kir4.1 underlies neuronal hyperexcitability and several behavioral defects in Fmr1 knockout mice. Viral delivery of Kir4.1 channels specifically to hippocampal astrocytes from Fmr1 knockout mice indeed rescues normal astrocyte potassium uptake, neuronal excitability, and cognitive and social performance. Our findings uncover an important role for astrocyte dysfunction in the pathophysiology of FXS, and identify Kir4.1 channel as a potential therapeutic target for FXS.

PGC-1α integrates insulin signaling with mitochondrial physiology and behavior in a Drosophila model of Fragile X Syndrome

Fragile X Syndrome (FXS) is the most prevalent monogenetic form of intellectual disability and autism. Recently, dysregulation of insulin signaling (IS) and aberrations in mitochondrial function have emerged as robust, evolutionarily conserved components of FXS pathophysiology. However, the mechanisms by which altered IS and mitochondrial dysfunction impact behavior in the context of FXS remain elusive. Here, we show that normalization of IS improves mitochondrial volume and function in flies that lack expression of dfmr1, the Drosophila homolog of the causal gene of FXS in humans. Further, we demonstrate that dysregulation of IS underlies diminished expression of the mitochondrial master regulator PGC-1α/Spargel in dfmr1 mutant flies. These results are behaviorally relevant, as we show that pan-neuronal augmentation of PGC-1α/Spargel improves circadian behavior in dfmr1 mutants. Notably, we also show that modulation of PGC-1α/Spargel expression in wild-type flies phenocopies the dfmr1 mutant circadian defect. Taken together, the results presented herein provide a mechanistic link between mitochondrial function and circadian behavior both in FXS pathogenesis as well as more broadly at the interface between metabolism and behavioral output.

Investigating cell-specific effects of FMRP deficiency on spiny projection neurons in a mouse model of Fragile X syndrome.

Fragile X syndrome (FXS), resulting from a mutation in the Fmr1 gene, is the most common monogenic cause of autism and inherited intellectual disability. Fmr1 encodes the Fragile X Messenger Ribonucleoprotein (FMRP), and its absence leads to cognitive, emotional, and social deficits compatible with the nucleus accumbens (NAc) dysfunction. This structure is pivotal in social behavior control, consisting mainly of spiny projection neurons (SPNs), distinguished by dopamine D1 or D2 receptor expression, connectivity, and associated behavioral functions. This study aims to examine how FMRP absence differentially affects SPN cellular properties, which is crucial for categorizing FXS cellular endophenotypes. We utilized a novel Fmr1-/y::Drd1a-tdTomato mouse model, which allows in-situ identification of SPN subtypes in FXS mice. Using RNA-sequencing, RNAScope and ex-vivo patch-clamp in adult male mice NAc, we comprehensively compared the intrinsic passive and active properties of SPN subtypes. Fmr1 transcripts and their gene product, FMRP, were found in both SPNs subtypes, indicating potential cell-specific functions for Fmr1. The study found that the distinguishing membrane properties and action potential kinetics typically separating D1- from D2-SPNs in wild-type mice were either reversed or abolished in Fmr1-/y::Drd1a-tdTomato mice. Interestingly, multivariate analysis highlighted the compound effects of Fmr1 ablation by disclosing how the phenotypic traits distinguishing each cell type in wild-type mice were altered in FXS. Our results suggest that the absence of FMRP disrupts the standard dichotomy characterizing NAc D1- and D2-SPNs, resulting in a homogenous phenotype. This shift in cellular properties could potentially underpin select aspects of the pathology observed in FXS. Therefore, understanding the nuanced effects of FMRP absence on SPN subtypes can offer valuable insights into the pathophysiology of FXS, opening avenues for potential therapeutic strategies.

From circuits to behavior: Amygdala dysfunction in fragile X syndrome.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a repeat expansion mutation in the promotor region of the FMR1 gene resulting in transcriptional silencing and loss of function of fragile X messenger ribonucleoprotein 1 protein (FMRP). FMRP has a well-defined role in the early development of the brain. Thus, loss of the FMRP has well-known consequences for normal cellular and synaptic development leading to a variety of neuropsychiatric disorders including an increased prevalence of amygdala-based disorders. Despite our detailed understanding of the pathophysiology of FXS, the precise cellular and circuit-level underpinnings of amygdala-based disorders is incompletely understood. In this review, we discuss the development of the amygdala, the role of neuromodulation in the critical period plasticity, and recent advances in our understanding of how synaptic and circuit-level changes in the basolateral amygdala contribute to the behavioral manifestations seen in FXS.

Across Dimensions: Developing 2D and 3D Human iPSC-Based Models of Fragile X Syndrome.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder. FXS is caused by a cytosine-guanine-guanine (CGG) trinucleotide repeat expansion in the untranslated region of the FMR1 gene leading to the functional loss of the gene’s protein product FMRP. Various animal models of FXS have provided substantial knowledge about the disorder. However, critical limitations exist in replicating the pathophysiological mechanisms. Human induced pluripotent stem cells (hiPSCs) provide a unique means of studying the features and processes of both normal and abnormal human neurodevelopment in large sample quantities in a controlled setting. Human iPSC-based models of FXS have offered a better understanding of FXS pathophysiology specific to humans. This review summarizes studies that have used hiPSC-based two-dimensional cellular models of FXS to reproduce the pathology, examine altered gene expression and translation, determine the functions and targets of FMRP, characterize the neurodevelopmental phenotypes and electrophysiological features, and, finally, to reactivate FMR1. We also provide an overview of the most recent studies using three-dimensional human brain organoids of FXS and end with a discussion of current limitations and future directions for FXS research using hiPSCs.

Genome-wide screening for genes involved in the epigenetic basis of fragile X syndrome.

SummaryFragile X syndrome (FXS), the most prevalent heritable form of intellectual disability, is caused by the transcriptional silencing of the FMR1 gene. The epigenetic factors responsible for FMR1 inactivation are largely unknown. Here, we initially demonstrated the feasibility of FMR1 reactivation by targeting a single epigenetic factor, DNMT1. Next, we established a model system for FMR1 silencing using a construct containing the FXS-related mutation upstream to a reporter gene. This construct was methylated in vitro and introduced into a genome-wide loss-of-function (LOF) library established in haploid human pluripotent stem cells (PSCs), allowing the identification of genes whose functional loss reversed the methylation-induced silencing of the FMR1 reporter. Selected candidate genes were further analyzed in haploid- and FXS-patient-derived PSCs, highlighting the epigenetic and metabolic pathways involved in FMR1 regulation. Our work sheds light on the mechanisms responsible for CGG-expansion-mediated FMR1 inactivation and offers novel targets for therapeutic FMR1 reactivation.

Association of lipid rafts cholesterol with clinical profile in fragile X syndrome

Fragile X syndrome (FXS) is the most prevalent monogenic cause of intellectual disability and autism spectrum disorder (ASD). Affected individuals have a high prevalence of hypocholesterolemia, however, the underlying mechanisms and the clinical significance remains unknown. We hypothesized that decrease in the plasma cholesterol levels is associated with an alteration of cholesterol content within the lipid rafts (LRs) which ultimately affects the clinical profile of FXS individuals. The platelets LRs were isolated by ultracentrifugation on sucrose gradient from 27 FXS and 25 healthy controls, followed by measurements of proteins, cholesterol, and gangliosides content. Autistic and adaptive behaviour of affected individuals were respectively assessed by the Social Communication Questionnaire and Adaptive Behavior Assessment System. Our results suggest a decrease in the cholesterol content of LRs in FXS individuals as compared to controls. As opposed to controls, LR cholesterol was significantly associated with plasma total cholesterol (r = 0.47; p = 0.042) in the FXS group. Furthermore, the correlation between LRs cholesterol and the clinical profile showed a significant association with autistic traits (r = − 0.67; p < 0.001) and adaptative behavior (r = 0.70; p < 0.001). These results support the clinical significance of LR cholesterol alterations in FXS. Further studies are warranted to investigate the implication of LRs in FXS pathophysiology and ASD.

Hyperexcitability and Homeostasis in Fragile X Syndrome.

Fragile X Syndrome (FXS) is a leading inherited cause of autism and intellectual disability, resulting from a mutation in the FMR1 gene and subsequent loss of its protein product FMRP. Despite this simple genetic origin, FXS is a phenotypically complex disorder with a range of physical and neurocognitive disruptions. While numerous molecular and cellular pathways are affected by FMRP loss, there is growing evidence that circuit hyperexcitability may be a common convergence point that can account for many of the wide-ranging phenotypes seen in FXS. The mechanisms for hyperexcitability in FXS include alterations to excitatory synaptic function and connectivity, reduced inhibitory neuron activity, as well as changes to ion channel expression and conductance. However, understanding the impact of FMR1 mutation on circuit function is complicated by the inherent plasticity in neural circuits, which display an array of homeostatic mechanisms to maintain activity near set levels. FMRP is also an important regulator of activity-dependent plasticity in the brain, meaning that dysregulated plasticity can be both a cause and consequence of hyperexcitable networks in FXS. This makes it difficult to separate the direct effects of FMR1 mutation from the myriad and pleiotropic compensatory changes associated with it, both of which are likely to contribute to FXS pathophysiology. Here we will: (1) review evidence for hyperexcitability and homeostatic plasticity phenotypes in FXS models, focusing on similarities/differences across brain regions, cell-types, and developmental time points; (2) examine how excitability and plasticity disruptions interact with each other to ultimately contribute to circuit dysfunction in FXS; and (3) discuss how these synaptic and circuit deficits contribute to disease-relevant behavioral phenotypes like epilepsy and sensory hypersensitivity. Through this discussion of where the current field stands, we aim to introduce perspectives moving forward in FXS research.

The Use of Peptides in the Treatment of Fragile X Syndrome: Challenges and Opportunities.

Fragile X Syndrome (FXS) is the most frequent cause of inherited intellectual disabilities and autism spectrum disorders, characterized by cognitive deficits and autistic behaviors. The silencing of the Fmr1 gene and consequent lack of FMRP protein, is the major contribution to FXS pathophysiology. FMRP is an RNA binding protein involved in the maturation and plasticity of synapses and its absence culminates in a range of morphological, synaptic and behavioral phenotypes. Currently, there are no approved medications for the treatment of FXS, with the approaches under study being fairly specific and unsatisfying in human trials. Here we propose peptides/peptidomimetics as candidates in the pharmacotherapy of FXS; in the last years this class of molecules has catalyzed the attention of pharmaceutical research, being highly selective and well-tolerated. Thanks to their ability to target protein-protein interactions (PPIs), they are already being tested for a wide range of diseases, including cancer, diabetes, inflammation, Alzheimer's disease, but this approach has never been applied to FXS. As FXS is at the forefront of efforts to develop new drugs and approaches, we discuss opportunities, challenges and potential issues of peptides/peptidomimetics in FXS drug design and development.

Correction of amygdalar dysfunction in a rat model of fragile X syndrome.

Fragile X syndrome (FXS), a commonly inherited form of autism and intellectual disability, is associated with emotional symptoms that implicate dysfunction of the amygdala. However, current understanding of the pathogenesis of the disease is based primarily on studies in the hippocampus and neocortex, where FXS defects have been corrected by inhibiting group I metabotropic glutamate receptors (mGluRs). Here, we observe that activation, rather than inhibition, of mGluRs in the basolateral amygdala reverses impairments in a rat model of FXS. FXS rats exhibit deficient recall of auditory conditioned fear, which is accompanied by a range of invitro and invivo deficits in synaptic transmission and plasticity. We find presynaptic mGluR5 in the amygdala, activation of which reverses deficient synaptic transmission and plasticity, thereby restoring normal fear learning in FXS rats. This highlights the importance of modifying the prevailing mGluR-based framework for therapeutic strategies to include circuit-specific differences in FXS pathophysiology.

Reciprocal regulation of spontaneous synaptic vesicle fusion by Fragile X mental retardation protein and group I metabotropic glutamate receptors.

Fragile X mental retardation protein (FMRP) is a neuronal protein mediating multiple functions, with its absence resulting in one of the most common monogenic causes of autism, Fragile X syndrome (FXS). Analyses of FXS pathophysiology have identified a range of aberrations in synaptic signaling pathways and plasticity associated with group I metabotropic glutamate (mGlu) receptors. These studies, however, have mostly focused on the post-synaptic functions of FMRP and mGlu receptor activation, and relatively little is known about their presynaptic effects. Neurotransmitter release is mediated via multiple forms of synaptic vesicle (SV) fusion, each of which contributes to specific neuronal functions. The impacts of mGlu receptor activation and loss of FMRP on these SV fusion events remain unexplored. Here we combined electrophysiological and fluorescence imaging analyses on primary hippocampal cultures prepared from an Fmr1 knockout (KO) rat model. Compared to wild-type (WT) hippocampal neurons, KO neurons displayed an increase in the frequency of spontaneous excitatory post-synaptic currents (sEPSCs), as well as spontaneous SV fusion events. Pharmacological activation of mGlu receptors in WT neurons caused a similar increase in spontaneous SV fusion and sEPSC frequency. Notably, this increase in SV fusion was not observed when spontaneous activity was blocked using the sodium channel antagonist tetrodotoxin. Importantly, the effect of mGlu receptor activation on spontaneous SV fusion was occluded in Fmr1 KO neurons. Together, our results reveal that FMRP represses spontaneous presynaptic SV fusion, whereas mGlu receptor activation increases this event. This reciprocal control appears to be mediated via their regulation of intrinsic neuronal excitability.

An "Omic" Overview of Fragile X Syndrome.

Simple SummaryFragile X syndrome (FXS) is a neurodevelopmental disorder and remains the most frequent inherited cause of intellectual disability. Fragile X patients are at great risk to develop behavior problems including autism, anxiety, aggressivity and hyperactivity. FXS results from a mutation leading to the absence of a single protein, the fragile X mental retardation protein (FMRP). Most studies aiming to understand the physiopathology of FXS are centered on the effect of its absence on protein synthesis. However, besides protein synthesis regulation, FMRP has several other functions that need to be understood and could play a significant role in FXS. The goal of the present work is to review some of these functions and to put them into perspective in order to get a more comprehensive understanding of FXS physiopathology.Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with a wide range of cognitive, behavioral and medical problems. It arises from the silencing of the fragile X mental retardation 1 (FMR1) gene and, consequently, in the absence of its encoded protein, FMRP (fragile X mental retardation protein). FMRP is a ubiquitously expressed and multifunctional RNA-binding protein, primarily considered as a translational regulator. Pre-clinical studies of the past two decades have therefore focused on this function to relate FMRP’s absence to the molecular mechanisms underlying FXS physiopathology. Based on these data, successful pharmacological strategies were developed to rescue fragile X phenotype in animal models. Unfortunately, these results did not translate into humans as clinical trials using same therapeutic approaches did not reach the expected outcomes. These failures highlight the need to put into perspective the different functions of FMRP in order to get a more comprehensive understanding of FXS pathophysiology. This work presents a review of FMRP’s involvement on noteworthy molecular mechanisms that may ultimately contribute to various biochemical alterations composing the fragile X phenotype.

Channelopathies in fragile X syndrome.

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading monogenic cause of autism. The condition stems from loss of fragile X mental retardation protein (FMRP), which regulates a wide range of ion channels via translational control, protein-protein interactions and second messenger pathways. Rapidly increasing evidence demonstrates that loss of FMRP leads to numerous ion channel dysfunctions (that is, channelopathies), which in turn contribute significantly to FXS pathophysiology. Consistent with this, pharmacological or genetic interventions that target dysregulated ion channels effectively restore neuronal excitability, synaptic function and behavioural phenotypes in FXS animal models. Recent studies further support a role for direct and rapid FMRP-channel interactions in regulating ion channel function. This Review lays out the current state of knowledge in the field regarding channelopathies and the pathogenesis of FXS, including promising therapeutic implications.

Fragile X mental retardation protein (FMRP) and metabotropic glutamate receptor subtype 5 (mGlu5) control stress granule formation in astrocytes

Fragile X syndrome (FXS) is a common form of intellectual disability and autism caused by the lack of Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein involved in RNA transport and protein synthesis. Upon cellular stress, global protein synthesis is blocked and mRNAs are recruited into stress granules (SGs), together with RNA-binding proteins including FMRP. Activation of group-I metabotropic glutamate (mGlu) receptors stimulates FMRP-mediated mRNA transport and protein synthesis, but their role in SGs formation is unexplored. To this aim, we pre-treated wild type (WT) and Fmr1 knockout (KO) cultured astrocytes with the group-I-mGlu receptor agonist (S)-3,5-Dihydroxyphenylglycine (DHPG) and exposed them to sodium arsenite (NaAsO2), a widely used inducer of SGs formation. In WT cultures the activation of group-I mGlu receptors reduced SGs formation and recruitment of FMRP into SGs, and also attenuated phosphorylation of eIF2α, a key event crucially involved in SGs formation and inhibition of protein synthesis. In contrast, Fmr1 KO astrocytes, which exhibited a lower number of SGs than WT astrocytes, did not respond to agonist stimulation. Interestingly, the mGlu5 receptor negative allosteric modulator (NAM) 2-methyl-6-(phenylethynyl)pyridine (MPEP) antagonized DHPG-mediated SGs reduction in WT and reversed SGs formation in Fmr1 KO cultures. Our findings reveal a novel function of mGlu5 receptor as modulator of SGs formation and open new perspectives for understanding cellular response to stress in FXS pathophysiology.

The safety and efficacy of metformin in fragile X syndrome: An open-label study

Fragile X syndrome (FXS) is a rare genetic disorder characterized by a deficit of the fragile X mental retardation protein (FMRP), encoded by the fragile X mental retardation gene (FMR1) on the X chromosome. It has been hypothesized that the absence of FRMP leads to higher levels of Insulin-like Growth Factor 1 (IGF-1) in the brain, possibly contributing to the intellectual impairment characteristic of the disorder. Preclinical studies have shown that metformin downregulates the insulin/IGF-1 signaling pathway, corrects dendritic defects, and improves repetitive behavior in Fmr1 knockout mice. Here, we conducted an open-label study to evaluate: (1) the safety of metformin in normoglycemic individuals with FXS; and (2) the efficacy of metformin to improve aberrant behavior, attention, and to modulate cortical functioning. Fifteen patients with FXS, aged from 17 to 44, received 500 mg of metformin twice/daily over a 9-week treatment period. The primary outcome measures were: (1) the incidence of adverse events (AE); (2) the decrease in IGF-1 levels; and (3) the global score of the Aberrant Behavior Checklist-Community, Fragile X. The secondary outcomes were: (1) the Test of Attentional Performance for children (KiTAP); and (2) the Transcranial Magnetic Stimulation (TMS) parameters measuring cortical excitability. The metformin treatment was well tolerated, with no significant related AE. The TMS data showed an increase in corticospinal inhibition mediated by GABAA and GABAB mechanisms. This study demonstrates the safety of metformin in normoglycemic patients with FXS, and suggests the potential of this medication in modifying GABA-mediated inhibition, a hallmark of FXS pathophysiology. Implications for future clinical trials are discussed.

Primary Ciliary Deficits in the Dentate Gyrus of Fragile X Syndrome.

SummaryThe primary cilium is the non-motile cilium present in most mammalian cell types and functions as an antenna for cells to sense signals. Ablating primary cilia in postnatal newborn neurons of the dentate gyrus (DG) results in both reduced dendritic arborization and synaptic strength, leading to hippocampal-dependent learning and memory deficits. Fragile X syndrome (FXS) is a common form of inheritance for intellectual disabilities with a high risk for autism spectrum disorders, and Fmr1 KO mice, a mouse model for FXS, demonstrate deficits in newborn neuron differentiation, dendritic morphology, and memory formation in the DG. Here, we found that the number of primary cilia in Fmr1 KO mice is reduced, specifically in the DG of the hippocampus. Moreover, this cilia loss was observed postnatally mainly in newborn neurons generated from the DG, implicating that these primary ciliary deficits may possibly contribute to the pathophysiology of FXS.

Multielectrode array analysis of EEG biomarkers in a mouse model of Fragile X Syndrome

Fragile X Syndrome (FXS) is a leading known genetic cause of intellectual disability with symptoms that include increased anxiety and social and sensory processing deficits. Recent EEG studies in humans with FXS have identified neural oscillation deficits that include increased resting state gamma power, increased amplitude of auditory evoked potentials, and reduced inter-trial phase coherence of sound-evoked gamma oscillations. Identification of comparable EEG biomarkers in mouse models of FXS could facilitate the pre-clinical to clinical therapeutic pipeline. However, while human EEG studies have involved 128-channel scalp EEG acquisition, no mouse studies have been performed with more than three EEG channels. In the current study, we employed a recently developed 30-channel mouse multielectrode array (MEA) system to record and analyze resting and stimulus-evoked EEG signals in WT vs. Fmr1 KO mice. Using this system, we now report robust MEA-derived phenotypes including higher resting EEG power, altered event-related potentials (ERPs) and reduced inter-trial phase coherence to auditory chirp stimuli in Fmr1 KO mice that are remarkably similar to those reported in humans with FXS. We propose that the MEA system can be used for: (i) derivation of higher-level EEG parameters; (ii) EEG biomarkers for drug testing; and (ii) mechanistic studies of FXS pathophysiology.