Region-Related Differences in Short-Term Synaptic Plasticity and Synaptotagmin-7 in the Male and Female Hippocampus of a Rat Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is an intellectual developmental disorder characterized, inter alia, by deficits in the short-term processing of neural information, such as sensory processing and working memory. The primary cause of FXS is the loss of fragile X messenger ribonucleoprotein (FMRP), which is profoundly involved in synaptic function and plasticity. Short-term synaptic plasticity (STSP) may play important roles in functions that are affected by FXS. Recent evidence points to the crucial involvement of the presynaptic calcium sensor synaptotagmin-7 (Syt-7) in STSP. However, how the loss of FMRP affects STSP and Syt-7 have been insufficiently studied. Furthermore, males and females are affected differently by FXS, but the underlying mechanisms remain elusive. The aim of the present study was to investigate possible changes in STSP and the expression of Syt-7 in the dorsal (DH) and ventral (VH) hippocampus of adult males and females in a Fmr1-knockout (KO) rat model of FXS. We found that the paired-pulse ratio (PPR) and frequency facilitation/depression (FF/D), two forms of STSP, as well as the expression of Syt-7, are normal in adult KO males, but the PPR is increased in the ventral hippocampus of KO females (6.4 ± 3.7 vs. 18.3 ± 4.2 at 25 ms in wild type (WT) and KO, respectively). Furthermore, we found no gender-related differences, but did find robust region-dependent difference in the STSP (e.g., the PPR at 50 ms: 50.0 ± 5.5 vs. 17.6 ± 2.9 in DH and VH of WT male rats; 53.1 ± 3.6 vs. 19.3 ± 4.6 in DH and VH of WT female rats; 48.1 ± 2.3 vs. 19.1 ± 3.3 in DH and VH of KO male rats; and 51.2 ± 3.3 vs. 24.7 ± 4.3 in DH and VH of KO female rats). AMPA receptors are similarly expressed in the two hippocampal segments of the two genotypes and in both genders. Also, basal excitatory synaptic transmission is higher in males compared to females. Interestingly, we found more than a twofold higher level of Syt-7, not synaptotagmin-1, in the dorsal compared to the ventral hippocampus in the males of both genotypes (0.43 ± 0.1 vs. 0.16 ± 0.02 in DH and VH of WT male rats, and 0.6 ± 0.13 vs. 0.23 ± 0.04 in DH and VH of KO male rats) and in the WT females (0.97 ± 0.23 vs. 0.31 ± 0.09 in DH and VH). These results point to the susceptibility of the female ventral hippocampus to FMRP loss. Importantly, the different levels of Syt-7, which parallel the higher score of the dorsal vs. ventral hippocampus on synaptic facilitation, suggest that Syt-7 may play a pivotal role in defining the striking differences in STSP along the long axis of the hippocampus.

Systemic pharmacological suppression of neural activity reverses learning impairment in a mouse model of Fragile X syndrome.

The enhancement of associative synaptic plasticity often results in impaired rather than enhanced learning. Previously, we proposed that such learning impairments can result from saturation of the plasticity mechanism (Nguyen-Vu et al., 2017), or, more generally, from a history-dependent change in the threshold for plasticity. This hypothesis was based on experimental results from mice lacking two class I major histocompatibility molecules, MHCI H2-Kb and H2-Db (MHCI KbDb-/-), which have enhanced associative long-term depression at the parallel fiber-Purkinje cell synapses in the cerebellum (PF-Purkinje cell LTD). Here, we extend this work by testing predictions of the threshold metaplasticity hypothesis in a second mouse line with enhanced PF-Purkinje cell LTD, the Fmr1 knockout mouse model of Fragile X syndrome (FXS). Mice lacking Fmr1 gene expression in cerebellar Purkinje cells (L7-Fmr1 KO) were selectively impaired on two oculomotor learning tasks in which PF-Purkinje cell LTD has been implicated, with no impairment on LTD-independent oculomotor learning tasks. Consistent with the threshold metaplasticity hypothesis, behavioral pre-training designed to reverse LTD at the PF-Purkinje cell synapses eliminated the oculomotor learning deficit in the L7-Fmr1 KO mice, as previously reported in MHCI KbDb-/-mice. In addition, diazepam treatment to suppress neural activity and thereby limit the induction of associative LTD during the pre-training period also eliminated the learning deficits in L7-Fmr1 KO mice. These results support the hypothesis that cerebellar LTD-dependent learning is governed by an experience-dependent sliding threshold for plasticity. An increased threshold for LTD in response to elevated neural activity would tend to oppose firing rate stability, but could serve to stabilize synaptic weights and recently acquired memories. The metaplasticity perspective could inform the development of new clinical approaches for addressing learning impairments in autism and other disorders of the nervous system.

Developmental associations between cognition and adaptive behavior in intellectual and developmental disability.

BACKGROUND: Intellectual and developmental disabilities (IDDs) are associated with both cognitive challenges and difficulties in conceptual, social, and practical areas of living, commonly referred to as adaptive behavior (DSM-5). Although cross-sectional associations between intelligence or cognition and adaptive behavior have been reported in IDD populations, no study to date has examined whether developmental changes in cognition contribute to or track with changes in adaptive behavior. The present study sought to examine associations of longitudinal developmental change in domains of cognition (NIH Toolbox Cognition Battery, NIHTB-CB) and adaptive behavior domains (Vineland Adaptive Behavior Scales-3; VABS-3) including Socialization, Communication, and Daily Living Skills (DLS) over a two year period in a large sample of children, adolescents and young adults with IDD. METHODS: Three groups were recruited, including those with fragile X syndrome, Down syndrome, and other/idiopathic intellectual disability. Eligible participants (n = 263) included those who were between 6 and 26 years (mage = 15.52, sd = 5.17) at Visit 1, and who had a diagnosis of, or suspected intellectual disability (ID), including borderline ID, with a mental age of at least 3.0 years. Participants were given cognitive and adaptive behavior assessments at two time points over a two year period (m = 2.45 years, range = 1.27 to 5.56 years). In order to examine the association of developmental change between cognitive and adaptive behavior domains, bivariate latent change score (BLCS) models were fit to compare change in the three cognitive domains measured by the NIHTB-CB (Fluid Cognition, Crystallized Cognition, Total Cognition) and the three adaptive behavior domains measured by the VABS-3 (Communication, DLS, and Socialization). RESULTS: Over a two year period, change in cognition (both Crystallized and Total Composites) was significantly and positively associated with change in daily living skills. Also, baseline cognition level predicted growth in adaptive behavior, however baseline adaptive behavior did not predict growth in cognition in any model. CONCLUSIONS: The present study demonstrated that developmental changes in cognition and adaptive behavior are associated in children and young adults with IDD, indicating the potential for cross-domain effects of intervention. Notably, improvements in DLS emerged as a primary area of adaptive behavior that positively related to improvements in cognition. This work provides evidence for the clinical, "real life" meaningfulness of changes in cognition detected by the NIHTB-CB in IDD, and provides empirical support for the NIHTB-CB as a fit-for-purpose performance-based outcome measure for this population.

From wings to whiskers to stem cells: why every model matters in fragile X syndrome research.

Fragile X syndrome (FXS) is caused by epigenetic silencing of the X-linked fragile X messenger ribonucleoprotein 1 (FMR1) gene located on chromosome Xq27.3, which leads to the loss of its protein product, fragile X messenger ribonucleoprotein (FMRP). It is the most prevalent inherited form of intellectual disability and the highest single genetic cause of autism. Since the discovery of the genetic basis of FXS, extensive studies using animal models and human pluripotent stem cells have unveiled the functions of FMRP and mechanisms underlying FXS. However, clinical trials have not yielded successful treatment. Here we review what we have learned from commonly used models for FXS, potential limitations of these models, and recommendations for future steps.

Adiponectin rescues synaptic plasticity in the dentate gyrus of a mouse model of Fragile X Syndrome.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is the leading known single-gene cause of autism spectrum disorder. Patients with FXS display varied behavioural deficits that include mild to severe cognitive impairments in addition to mood disorders. Currently, there is no cure for this condition; however, there is an emerging focus on therapies that inhibit mechanistic target of rapamycin (mTOR)-dependent protein synthesis owing to the clinical effectiveness of metformin for alleviating some behavioural symptoms in FXS. Adiponectin (APN) is a neurohormone that is released by adipocytes and provides an alternative means to inhibit mTOR activation in the brain. In these studies, we show that Fmr1 knockout mice, like patients with FXS, show reduced levels of circulating APN and that both long-term potentiation (LTP) and long-term depression (LTD) in the dentate gyrus (DG) are impaired. Brief (20 min) incubation of hippocampal slices in APN (50 nM) was able to rescue both LTP and LTD in the DG and increased both the surface expression and phosphorylation of GluA1 receptors. These results provide evidence for reduced APN levels in FXS playing a role in decreasing bidirectional synaptic plasticity and show that therapies which enhance APN levels may have therapeutic potential for this and related conditions.This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Cage effects on synaptic plasticity and its modulation in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is characterized by impairments in executive function including different types of learning and memory. Long-term potentiation (LTP), thought to underlie the formation of memories, has been studied in the Fmr1 mouse model of FXS. However, there have been many discrepancies in the literature with inconsistent use of littermate and non-littermate Fmr1 knockout (KO) and wild-type (WT) control mice. Here, the influence of the breeding strategy (cage effect) on short-term potentiation (STP), LTP, contextual fear conditioning (CFC), expression of N-methyl-d-aspartate receptor (NMDAR) subunits and the modulation of NMDARs, were examined. The largest deficits in STP, LTP and CFC were found in KO mice compared with non-littermate WT. However, the expression of NMDAR subunits was unchanged in this comparison. Rather, NMDAR subunit (GluN1, 2A, 2B) expression was sensitive to the cage effect, with decreased expression in both WT and KO littermates compared with non-littermates. Interestingly, an NMDAR-positive allosteric modulator, UBP714, was only effective in potentiating the induction of LTP in non-littermate KO mice and not the littermate KO mice. These results suggest that commonly studied phenotypes in Fmr1 KOs are sensitive to the cage effect and therefore the breeding strategy may contribute to discrepancies in the literature.This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Sex differences during development in cortical temporal processing and event related potentials in wild-type and fragile X syndrome model mice.

BACKGROUND: Autism spectrum disorder (ASD) is currently diagnosed in approximately 1 in 44 children in the United States, based on a wide array of symptoms, including sensory dysfunction and abnormal language development. Boys are diagnosed ~ 3.8 times more frequently than girls. Auditory temporal processing is crucial for speech recognition and language development. Abnormal development of temporal processing may account for ASD language impairments. Sex differences in the development of temporal processing may underlie the differences in language outcomes in male and female children with ASD. To understand mechanisms of potential sex differences in temporal processing requires a preclinical model. However, there are no studies that have addressed sex differences in temporal processing across development in any animal model of ASD. METHODS: To fill this major gap, we compared the development of auditory temporal processing in male and female wildtype (WT) and Fmr1 knock-out (KO) mice, a model of Fragile X Syndrome (FXS), a leading genetic cause of ASD-associated behaviors. Using epidural screw electrodes, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (ASSR) paradigm at young (postnatal (p)21 and p30) and adult (p60) ages from both auditory and frontal cortices of awake, freely moving mice. RESULTS: The results show that ERP amplitudes were enhanced in both sexes of Fmr1 KO mice across development compared to WT counterparts, with greater enhancement in adult female than adult male KO mice. Gap-ASSR deficits were seen in the frontal, but not auditory, cortex in early development (p21) in female KO mice. Unlike male KO mice, female KO mice show WT-like temporal processing at p30. There were no temporal processing deficits in the adult mice of both sexes. CONCLUSIONS: These results show a sex difference in the developmental trajectories of temporal processing and hypersensitive responses in Fmr1 KO mice. Male KO mice show slower maturation of temporal processing than females. Female KO mice show stronger hypersensitive responses than males later in development. The differences in maturation rates of temporal processing and hypersensitive responses during various critical periods of development may lead to sex differences in language function, arousal and anxiety in FXS.

Mitochondrial dysfunction in brain tissues and Extracellular Vesicles Fragile X-associated tremor/ataxia syndrome.

OBJECTIVE: Mitochondrial impairments have been implicated in the pathogenesis of Fragile X-associated tremor/ataxia syndrome (FXTAS) based on analysis of mitochondria in peripheral tissues and cultured cells. We sought to assess whether mitochondrial abnormalities present in postmortem brain tissues of patients with FXTAS are also present in plasma neuron-derived extracellular vesicles (NDEVs) from living carriers of fragile X messenger ribonucleoprotein1 (FMR1) gene premutations at an early asymptomatic stage of the disease continuum. METHODS: We utilized postmortem frozen cerebellar and frontal cortex samples from a cohort of eight patients with FXTAS and nine controls and measured the quantity and activity of the mitochondrial proteins complex IV and complex V. In addition, we evaluated the same measures in isolated plasma NDEVs by selective immunoaffinity capture targeting L1CAM from a separate cohort of eight FMR1 premutation carriers and four age-matched controls. RESULTS: Lower complex IV and V quantity and activity were observed in the cerebellum of FXTAS patients compared to controls, without any differences in total mitochondrial content. No patient-control differences were observed in the frontal cortex. In NDEVs, FMR1 premutation carriers compared to controls had lower activity of Complex IV and Complex V, but higher Complex V quantity. INTERPRETATION: Quantitative and functional abnormalities in mitochondrial electron transport chain complexes IV and V seen in the cerebellum of patients with FXTAS are also manifest in plasma NDEVs of FMR1 premutation carriers. Plasma NDEVs may provide further insights into mitochondrial pathologies in this syndrome and could potentially lead to the development of biomarkers for predicting symptomatic FXTAS among premutation carriers and disease monitoring.

Hypnotic treatment improves sleep architecture and EEG disruptions and rescues memory deficits in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is associated with disrupted cognition and sleep abnormalities. Sleep loss negatively impacts cognitive function, and one untested possibility is that disrupted cognition in FXS is exacerbated by abnormal sleep. We tested whether ML297, a hypnotic acting on G-protein-activated inward-rectifying potassium (GIRK) channels, could reverse sleep phenotypes and disrupted memory in Fmr1-/y mice. Fmr1-/y mice exhibit reduced non-rapid eye movement (NREM) sleep and fragmented NREM architecture, altered sleep electroencephalogram (EEG) oscillations, and reduced EEG coherence between cortical areas; these are partially reversed following ML297 administration. Treatment following contextual fear or spatial learning restores disrupted memory consolidation in Fmr1-/y mice. During memory recall, Fmr1-/y mice show an altered balance of activity among hippocampal principal neurons vs. parvalbumin-expressing interneurons; this is partially reversed by ML297. Because sleep disruption could impact neurophysiological phenotypes in FXS, augmenting sleep may improve disrupted cognition in this disorder.

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.

Role of fragile X messenger ribonucleoprotein 1 in the pathophysiology of brain disorders: a glia perspective.

Fragile X messenger ribonucleoprotein 1 (FMRP) is a widely expressed RNA binding protein involved in several steps of mRNA metabolism. Mutations in the FMR1 gene encoding FMRP are responsible for fragile X syndrome (FXS), a leading genetic cause of intellectual disability and autism spectrum disorder, and fragile X-associated tremor-ataxia syndrome (FXTAS), a neurodegenerative disorder in aging men. Although FMRP is mainly expressed in neurons, it is also present in glial cells and its deficiency or altered expression can affect functions of glial cells with implications for the pathophysiology of brain disorders. The present review focuses on recent advances on the role of glial subtypes, astrocytes, oligodendrocytes and microglia, in the pathophysiology of FXS and FXTAS, and describes how the absence or reduced expression of FMRP in these cells can impact on glial and neuronal functions. We will also briefly address the role of FMRP in radial glial cells and its effects on neural development, and gliomas and will speculate on the role of glial FMRP in other brain disorders.

Potential Prodromal Digital Postural Sway Markers for Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) Detected via Dual-Tasking and Sensory Manipulation.

FXTAS is a neurodegenerative disorder occurring in some Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene premutation carriers (PMCs) and is characterized by cerebellar ataxia, tremor, and cognitive deficits that negatively impact balance and gait and increase fall risk. Dual-tasking (DT) cognitive-motor paradigms and challenging balance conditions may have the capacity to reveal markers of FXTAS onset. Our objectives were to determine the impact of dual-tasking and sensory and stance manipulation on balance in FXTAS and potentially detect subtle postural sway deficits in FMR1 PMCs who are asymptomatic for signs of FXTAS on clinical exam. Participants with FXTAS, PMCs without FXTAS, and controls underwent balance testing using an inertial sensor system. Stance, vision, surface stability, and cognitive demand were manipulated in 30 s trials. FXTAS participants had significantly greater total sway area, jerk, and RMS sway than controls under almost all balance conditions but were most impaired in those requiring vestibular control. PMCs without FXTAS had significantly greater RMS sway compared with controls in the feet apart, firm, single task conditions both with eyes open and closed (EC) and the feet together, firm, EC, DT condition. Postural sway deficits in the RMS postural sway variability domain in asymptomatic PMCs might represent prodromal signs of FXTAS. This information may be useful in providing sensitive biomarkers of FXTAS onset and as quantitative balance measures in future interventional trials and longitudinal natural history studies.

Dysfunctions of cellular context-sensitivity in neurodevelopmental learning disabilities.

Pyramidal neurons have a pivotal role in the cognitive capabilities of neocortex. Though they have been predominantly modeled as integrate-and-fire point processors, many of them have another point of input integration in their apical dendrites that is central to mechanisms endowing them with the sensitivity to context that underlies basic cognitive capabilities. Here we review evidence implicating impairments of those mechanisms in three major neurodevelopmental disabilities, fragile X, Down syndrome, and fetal alcohol spectrum disorders. Multiple dysfunctions of the mechanisms by which pyramidal cells are sensitive to context are found to be implicated in all three syndromes. Further deciphering of these cellular mechanisms would lead to the understanding of and therapies for learning disabilities beyond any that are currently available.

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.

Topography and Ensemble Activity in the Auditory Cortex of a Mouse Model of Fragile X Syndrome.

Autism spectrum disorder (ASD) is often associated with social communication impairments and specific sound processing deficits, for example, problems in following speech in noisy environments. To investigate underlying neuronal processing defects located in the auditory cortex (AC), we performed two-photon Ca2+ imaging in FMR1 (fragile X messenger ribonucleoprotein 1) knock-out (KO) mice, a model for fragile X syndrome (FXS), the most common cause of hereditary ASD in humans. For primary AC (A1) and the anterior auditory field (AAF), topographic frequency representation was less ordered compared with control animals. We additionally analyzed ensemble AC activity in response to various sounds and found subfield-specific differences. In A1, ensemble correlations were lower in general, while in secondary AC (A2), correlations were higher in response to complex sounds, but not to pure tones. Furthermore, sound specificity of ensemble activity was decreased in AAF. Repeating these experiments 1 week later revealed no major differences regarding representational drift. Nevertheless, we found subfield- and genotype-specific changes in ensemble correlation values between the two times points, hinting at alterations in network stability in FMR1 KO mice. These detailed insights into AC network activity and topography in FMR1 KO mice add to the understanding of auditory processing defects in FXS.

Calcium-Dependent Regulation of Neuronal Excitability Is Rescued in Fragile X Syndrome by a Tat-Conjugated N-Terminal Fragment of FMRP.

Fragile X syndrome (FXS) arises from the loss of fragile X messenger ribonucleoprotein (FMRP) needed for normal neuronal excitability and circuit functions. Recent work revealed that FMRP contributes to mossy fiber long-term potentiation by adjusting the Kv4 A-type current availability through interactions with a Cav3-Kv4 ion channel complex, yet the mechanism has not yet been defined. In this study using wild-type and Fmr1 knock-out (KO) tsA-201 cells and cerebellar sections from male Fmr1 KO mice, we show that FMRP associates with all subunits of the Cav3.1-Kv4.3-KChIP3 complex and is critical to enabling calcium-dependent shifts in Kv4.3 inactivation to modulate the A-type current. Specifically, upon depolarization Cav3 calcium influx activates dual-specific phosphatase 1/6 (DUSP1/6) to deactivate ERK1/2 (ERK) and lower phosphorylation of Kv4.3, a signaling pathway that does not function in Fmr1 KO cells. In Fmr1 KO mouse tissue slices, cerebellar granule cells exhibit a hyperexcitable response to membrane depolarizations. Either incubating Fmr1 KO cells or in vivo administration of a tat-conjugated FMRP N-terminus fragment (FMRP-N-tat) rescued Cav3-Kv4 function and granule cell excitability, with a decrease in the level of DUSP6. Together these data reveal a Cav3-activated DUSP signaling pathway critical to the function of a FMRP-Cav3-Kv4 complex that is misregulated in Fmr1 KO conditions. Moreover, FMRP-N-tat restores function of this complex to rescue calcium-dependent control of neuronal excitability as a potential therapeutic approach to alleviating the symptoms of FXS.

Selective vulnerability of the ventral hippocampus-prelimbic cortex axis parvalbumin interneuron network underlies learning deficits of fragile X mice.

High-penetrance mutations affecting mental health can involve genes ubiquitously expressed in the brain. Whether the specific patterns of dysfunctions result from ubiquitous circuit deficits or might reflect selective vulnerabilities of targetable subnetworks has remained unclear. Here, we determine how loss of ubiquitously expressed fragile X mental retardation protein (FMRP), the cause of fragile X syndrome, affects brain networks in Fmr1y/- mice. We find that in wild-type mice, area-specific knockout of FMRP in the adult mimics behavioral consequences of area-specific silencing. By contrast, the functional axis linking the ventral hippocampus (vH) to the prelimbic cortex (PreL) is selectively affected in constitutive Fmr1y/- mice. A chronic alteration in late-born parvalbumin interneuron networks across the vH-PreL axis rescued by VIP signaling specifically accounts for deficits in vH-PreL theta-band network coherence, ensemble assembly, and learning functions of Fmr1y/- mice. Therefore, vH-PreL axis function exhibits a selective vulnerability to loss of FMRP in the vH or PreL, leading to learning and memory dysfunctions in fragile X mice.

Phenotypic analysis of multielectrode array EEG biomarkers in developing and adult male Fmr1 KO mice.

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 electroencephalographic (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 phase locking of sound-evoked gamma oscillations. Similar EEG phenotypes are present in mouse models of FXS, but very little is known about the development of such abnormal responses. In the current study, we employed a 30-channel mouse multielectrode array (MEA) system to record and analyze resting and stimulus-evoked EEG signals in male P21 and P91 WT and Fmr1 KO mice. This led to several novel findings. First, P91, but not P21, Fmr1 KO mice have significantly increased resting EEG power in the low- and high-gamma frequency bands. Second, both P21 and P91 Fmr1 KO mice have markedly attenuated inter-trial phase coherence (ITPC) to spectrotemporally dynamic auditory stimuli as well as to 40 Hz and 80 Hz auditory steady-state response (ASSR) stimuli. This suggests abnormal temporal processing from early development that may lead to abnormal speech and language function in FXS. Third, we found hemispheric asymmetry of fast temporal processing in the mouse auditory cortex in WT but not Fmr1 KO mice. Together, these findings define a set of EEG phenotypes in young and adult mice that can serve as translational targets for genetic and pharmacological manipulation in phenotypic rescue studies.

Hemispheric Utilization of Alpha Oscillatory Dynamics as a Unique Biomarker of Neural Compensation in Females with Fragile X Syndrome.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a trinucleotide expansion on the FMR1 gene and characterized by intellectual disability, sensory hypersensitivity, executive function difficulties, and social anxiety. Recently, efforts to define neural biomarkers for FXS have highlighted disruptions to power in the alpha frequency band; however the dynamic mechanisms supporting these findings are poorly understood. The current study aimed to explore the temporal and hemispheric dynamics supporting alpha phenotypes in FXS and their relationship with neural phenotypes related to auditory processing using electroencephalography during an auditory evoked task. Adolescents and adults (N = 36) with FXS and age/sex matched typically developing controls (N = 40) completed an auditory chirp task. Frontal alpha power in the prestimulus period was decomposed into "bursts" using percentile thresholding, then assessed for number of bursts per second (burst count) and burst length. Data were compared across left and right hemispheres to assess lateralization of neural activity. Individuals with FXS showed more differences in alpha power compared to TDC primarily in the right hemisphere. Notably, alpha hemisphere outcomes in males with FXS were driven by the number of times they entered a dynamically relevant period of alpha (burst count) rather than length of time spent in alpha. Females with FXS showed reduced burst counts but remained in sustained high alpha states for longer periods of time. Length of time spent in alpha may reflect a modulatory or compensatory mechanism capable of recovering sensory processing abilities in females with FXS resulting in a less severe clinical presentation. Right hemisphere abnormalities may impact sensory processing differences between males and females with FXS. The relationship between alpha burst length, count, sex, and hemisphere may shed light on underlying mechanisms for previously observed alpha power abnormalities in FXS and their variation by sex.

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 in vitro and in vivo 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.