scholarly journals Experience-dependent weakening of callosal synaptic connections in the absence of postsynaptic FMRP

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Zhe Zhang ◽  
Jay R Gibson ◽  
Kimberly M Huber
Keyword(s):  
Fragile X ◽  
Sensory Deprivation ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Excitatory Synapses ◽  
Loss Of Function ◽  
Cortical Circuits ◽  
Interhemispheric Connectivity ◽  
Direct Cell ◽  
Input Strength

Reduced structural and functional interhemispheric connectivity correlates with the severity of Autism Spectrum Disorder (ASD) behaviors in humans. Little is known of how ASD-risk genes regulate callosal connectivity. Here we show that Fmr1, whose loss-of-function leads to Fragile X Syndrome (FXS), cell autonomously promotes maturation of callosal excitatory synapses between somatosensory barrel cortices in mice. Postnatal, cell-autonomous deletion of Fmr1 in postsynaptic Layer (L) 2/3 or L5 neurons results in a selective weakening of AMPA receptor- (R), but not NMDA receptor-, mediated callosal synaptic function, indicative of immature synapses. Sensory deprivation by contralateral whisker trimming normalizes callosal input strength, suggesting that experience-driven activity of postsynaptic Fmr1 KO L2/3 neurons weakens callosal synapses. In contrast to callosal inputs, synapses originating from local L4 and L2/3 circuits are normal, revealing an input-specific role for postsynaptic Fmr1 in regulation of synaptic connectivity within local and callosal neocortical circuits. These results suggest direct cell autonomous and postnatal roles for FMRP in development of specific cortical circuits and suggest a synaptic basis for long-range functional underconnectivity observed in FXS patients.

scholarly journals FMRP regulates experience-dependent maturation of callosal synaptic connections and bilateral cortical synchrony

2021 ◽  
Author(s):  
Zhe Zhang ◽  
Jeffrey Rumschlag ◽  
Carrie R Jonak ◽  
Devin K Binder ◽  
Khaleel A Razak ◽  
...  
Keyword(s):  
Fragile X ◽  
Sensory Deprivation ◽  
Sensory Stimulation ◽  
Brain Dysfunction ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Excitatory Synapses ◽  
Loss Of Function ◽  
Interhemispheric Connectivity ◽  
Eeg Recordings

Reduced structural and functional interhemispheric connectivity correlates with the severity Autism Spectrum Disorder (ASD) behaviors in humans. Little is known of how ASD-risk genes regulate callosal connectivity. Here we show that Fmr1, whose loss-of-function leads to Fragile X Syndrome (FXS), cell autonomously promotes maturation of callosal excitatory synapses between somatosensory barrel cortices. Postnatal, cell-autonomous deletion of Fmr1 in postsynaptic Layer (L) 2/3 or L5 neurons results in a selective weakening of AMPA receptor- (R), but not NMDA receptor-, mediated synaptic function, indicative of increased 'silent', or immature, callosal synapses. Sensory deprivation by contralateral whisker trimming normalizes callosal input strength, suggesting that experience-driven activity of postsynaptic Fmr1 KO L2/3 neurons weakens callosal synapses. In contrast to callosal inputs, synapses originating from local L4 and L2/3 circuits are normal, revealing an input-specific role for postsynaptic Fmr1 in promoting callosal synaptic connectivity. Multielectrode EEG recordings in awake Fmr1 KO mice find reduced coherence of bilateral neural oscillations in beta and gamma frequencies during rest and sensory stimulation, reflecting reduced interhemispheric integration. Our findings reveal the cellular and synaptic mechanisms by which loss of Fmr1 leads to reduced interhemispheric connectivity and suggests a novel biomarker of brain dysfunction in FXS.

scholarly journals Hyperexcitability and loss of feedforward inhibition in the Fmr1KO lateral amygdala

2020 ◽  
Author(s):  
E. Mae Guthman ◽  
Matthew N. Svalina ◽  
Christian A. Cea-Del Rio ◽  
J. Keenan Kushner ◽  
Serapio M. Baca ◽  
...  
Keyword(s):  
Anxiety Disorders ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Excitatory Synapses ◽  
Lateral Amygdala ◽  
Early Postnatal Development ◽  
Whole Cell Patch Clamp ◽  
Patch Clamp Electrophysiology

SummaryFragile X Syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disability, autism spectrum disorders (ASDs), and anxiety disorders. The disruption in the function of the FMR1 gene results in a range of alterations in cellular and synaptic function. Previous studies have identified dynamic alterations in inhibitory neurotransmission in early postnatal development in the amygdala of the mouse model of FXS. Yet little is known how these changes alter microcircuit development and plasticity in the lateral amygdala (LA). Using whole-cell patch clamp electrophysiology, we demonstrate that principal neurons (PNs) in the LA exhibit hyperexcitability with a concomitant increase in the synaptic strength of excitatory synapses in the BLA. Further, reduced feed-forward inhibition appears to enhance synaptic plasticity in the FXS amygdala. These results demonstrate that plasticity is enhanced in the amygdala of the juvenile Fmr1 KO mouse and that E/I imbalance may underpin anxiety disorders commonly seen in FXS and ASDs.

scholarly journals Metabotropic Glutamate Receptor–Mediated Use–Dependent Down-Regulation of Synaptic Excitability Involves the Fragile X Mental Retardation Protein

2009 ◽  
Vol 101 (2) ◽  
pp. 672-687 ◽  
Author(s):  
Sarah Repicky ◽  
Kendal Broadie
Keyword(s):  
Mental Retardation ◽  
Glutamate Receptor ◽  
High Frequency ◽  
Metabotropic Glutamate Receptor ◽  
Fragile X ◽  
Protein Translation ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
High Frequency Stimulation ◽  
Metabotropic Glutamate

Loss of the mRNA-binding protein FMRP results in the most common inherited form of both mental retardation and autism spectrum disorders: fragile X syndrome (FXS). The leading FXS hypothesis proposes that metabotropic glutamate receptor (mGluR) signaling at the synapse controls FMRP function in the regulation of local protein translation to modulate synaptic transmission strength. In this study, we use the Drosophila FXS disease model to test the relationship between Drosophila FMRP (dFMRP) and the sole Drosophila mGluR (dmGluRA) in regulation of synaptic function, using two-electrode voltage-clamp recording at the glutamatergic neuromuscular junction (NMJ). Null dmGluRA mutants show minimal changes in basal synapse properties but pronounced defects during sustained high-frequency stimulation (HFS). The double null dfmr1;dmGluRA mutant shows repression of enhanced augmentation and delayed onset of premature long-term facilitation (LTF) and strongly reduces grossly elevated post-tetanic potentiation (PTP) phenotypes present in dmGluRA-null animals. Null dfmr1 mutants show features of synaptic hyperexcitability, including multiple transmission events in response to a single stimulus and cyclic modulation of transmission amplitude during prolonged HFS. The double null dfmr1;dmGluRA mutant shows amelioration of these defects but does not fully restore wildtype properties in dfmr1-null animals. These data suggest that dmGluRA functions in a negative feedback loop in which excess glutamate released during high-frequency transmission binds the glutamate receptor to dampen synaptic excitability, and dFMRP functions to suppress the translation of proteins regulating this synaptic excitability. Removal of the translational regulator partially compensates for loss of the receptor and, similarly, loss of the receptor weakly compensates for loss of the translational regulator.

scholarly journals The Role of Alpha-Synuclein And Other Parkinson’s Genes in Neurodevelopmental and Neurodegenerative Disorders

2020 ◽  
Author(s):  
C. Alejandra Morato Torres ◽  
Zinah Wassouf ◽  
Faria Zafar ◽  
Danuta Sastre ◽  
Tiago Fleming Outeiro ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Fragile X ◽  
Autism Spectrum ◽  
Alpha Synuclein ◽  
Synaptic Function ◽  
Chromosome 22Q11 ◽  
Causal Variants ◽  
Genomic Regions

Neurodevelopmental and late-onset neurodegenerative disorders present as separate entities that are clinically and neuropathologically quite distinct. However, recent evidence has highlighted surprising commonalities and converging features at the clinical, genomic, and molecular level between these two disease spectra. This is particularly striking in the context of autism spectrum disorder (ASD) and Parkinson’s disease (PD). Genetic causes and risk factors play a central role in disease pathophysiology and enable the identification of overlapping mechanisms and pathways. Here, we focus on clinico-genetic studies of causal variants and overlapping clinical and cellular features of ASD and PD. Several genes and genomic regions were selected for our review, including SNCA (alpha-synuclein), PARK2 (parkin RBR E3 ubiquitin protein ligase), chromosome 22q11 deletion/DiGeorge region, and FMR1 (fragile X mental retardation 1) repeat expansion, which influence development of both ASD and PD with converging features related to synaptic function and neurogenesis. Both PD and ASD display alterations and impairments at the synaptic level, representing early and key disease phenotypes which support the hypothesis of converging mechanisms between the two types of diseases. Therefore, understanding the underlying molecular mechanisms might inform on common targets and therapeutic approaches. We propose to re-conceptualize how we understand these disorders and provide a new angle into disease targets and mechanisms linking neurodevelopmental disorders and neurodegeneration.

scholarly journals Hyaluronan regulates synapse formation and function in developing neural networks

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Emily Wilson ◽  
Warren Knudson ◽  
Karen Newell-Litwa
Keyword(s):  
Extracellular Matrix ◽  
Brain Development ◽  
Synapse Formation ◽  
Autism Spectrum ◽  
Inhibitory Synapse ◽  
Synaptic Function ◽  
Excitatory Synapse ◽  
Network Activity ◽  
Excitatory Synapses ◽  
Inhibitory Signaling

Abstract Neurodevelopmental disorders present with synaptic alterations that disrupt the balance between excitatory and inhibitory signaling. For example, hyperexcitability of cortical neurons is associated with both epilepsy and autism spectrum disorders. However, the mechanisms that initially establish the balance between excitatory and inhibitory signaling in brain development are not well understood. Here, we sought to determine how the extracellular matrix directs synapse formation and regulates synaptic function in a model of human cortical brain development. The extracellular matrix, making up twenty percent of brain volume, is largely comprised of hyaluronan. Hyaluronan acts as both a scaffold of the extracellular matrix and a space-filling molecule. Hyaluronan is present from the onset of brain development, beginning with neural crest cell migration. Through acute perturbation of hyaluronan levels during synaptogenesis, we sought to determine how hyaluronan impacts the ratio of excitatory to inhibitory synapse formation and the resulting neural activity. We used 3-D cortical spheroids derived from human induced pluripotent stem cells to replicate this neurodevelopmental window. Our results demonstrate that hyaluronan preferentially surrounds nascent excitatory synapses. Removal of hyaluronan increases the expression of excitatory synapse markers and results in a corresponding increase in the formation of excitatory synapses, while also decreasing inhibitory synapse formation. This increased excitatory synapse formation elevates network activity, as demonstrated by microelectrode array analysis. In contrast, the addition of purified hyaluronan suppresses excitatory synapse formation. These results establish that the hyaluronan extracellular matrix surrounds developing excitatory synapses, where it critically regulates synapse formation and the resulting balance between excitatory to inhibitory signaling.

scholarly journals FMR1 and Autism, an Intriguing Connection Revisited

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1218
Author(s):  
William Fyke ◽  
Milen Velinov
Keyword(s):  
Fragile X ◽  
Major Gene ◽  
Single Gene ◽  
Autism Spectrum ◽  
Protein Product ◽  
Loss Of Function ◽  
Cgg Repeat ◽  
Statistical Manual ◽  
The Us ◽  
The Central Nervous System

Autism Spectrum Disorder (ASD) represents a distinct phenotype of behavioral dysfunction that includes deficiencies in communication and stereotypic behaviors. ASD affects about 2% of the US population. It is a highly heritable spectrum of conditions with substantial genetic heterogeneity. To date, mutations in over 100 genes have been reported in association with ASD phenotypes. Fragile X syndrome (FXS) is the most common single-gene disorder associated with ASD. The gene associated with FXS, FMR1 is located on chromosome X. Accordingly, the condition has more severe manifestations in males. FXS results from the loss of function of FMR1 due to the expansion of an unstable CGG repeat located in the 5′′ untranslated region of the gene. About 50% of the FXS males and 20% of the FXS females meet the Diagnostic Statistical Manual 5 (DSM-5) criteria for ASD. Among the individuals with ASD, about 3% test positive for FXS. FMRP, the protein product of FMR1, is a major gene regulator in the central nervous system. Multiple pathways regulated by FMRP are found to be dysfunctional in ASD patients who do not have FXS. Thus, FXS presents the opportunity to study cellular phenomena that may have wider applications in the management of ASD and to develop new strategies for ASD therapy.

scholarly journals Effects of the sigma-1 receptor agonist blarcamesine in a murine model of fragile X syndrome: neurobehavioral phenotypes and receptor occupancy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Samantha T. Reyes ◽  
Robert M. J. Deacon ◽  
Scarlett G. Guo ◽  
Francisco J. Altimiras ◽  
Jessa B. Castillo ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Neurodevelopmental Disorders ◽  
Fragile X ◽  
Regional Distribution ◽  
Receptor Occupancy ◽  
Autism Spectrum ◽  
Contextual Fear Conditioning ◽  
Synaptic Function ◽  
Sigma 1 Receptor ◽  
Sigma 1

AbstractFragile X syndrome (FXS), a disorder of synaptic development and function, is the most prevalent genetic form of intellectual disability and autism spectrum disorder. FXS mouse models display clinically-relevant phenotypes, such as increased anxiety and hyperactivity. Despite their availability, so far advances in drug development have not yielded new treatments. Therefore, testing novel drugs that can ameliorate FXS’ cognitive and behavioral impairments is imperative. ANAVEX2-73 (blarcamesine) is a sigma-1 receptor (S1R) agonist with a strong safety record and preliminary efficacy evidence in patients with Alzheimer’s disease and Rett syndrome, other synaptic neurodegenerative and neurodevelopmental disorders. S1R’s role in calcium homeostasis and mitochondrial function, cellular functions related to synaptic function, makes blarcamesine a potential drug candidate for FXS. Administration of blarcamesine in 2-month-old FXS and wild type mice for 2 weeks led to normalization in two key neurobehavioral phenotypes: open field test (hyperactivity) and contextual fear conditioning (associative learning). Furthermore, there was improvement in marble-burying (anxiety, perseverative behavior). It also restored levels of BDNF, a converging point of many synaptic regulators, in the hippocampus. Positron emission tomography (PET) and ex vivo autoradiographic studies, using the highly selective S1R PET ligand [18F]FTC-146, demonstrated the drug’s dose-dependent receptor occupancy. Subsequent analyses also showed a wide but variable brain regional distribution of S1Rs, which was preserved in FXS mice. Altogether, these neurobehavioral, biochemical, and imaging data demonstrates doses that yield measurable receptor occupancy are effective for improving the synaptic and behavioral phenotype in FXS mice. The present findings support the viability of S1R as a therapeutic target in FXS, and the clinical potential of blarcamesine in FXS and other neurodevelopmental disorders.

scholarly journals Autism Spectrum Disorders: Multiple Routes to, and Multiple Consequences of, Abnormal Synaptic Function and Connectivity

2020 ◽  
pp. 107385842092137 ◽  
Author(s):  
Liam Carroll ◽  
Sven Braeutigam ◽  
John M. Dawes ◽  
Zeljka Krsnik ◽  
Ivica Kostovic ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Fragile X ◽  
Autism Spectrum ◽  
Postnatal Period ◽  
Synaptic Function ◽  
Synaptic Dysfunction ◽  
Brain Areas ◽  
Multiple Routes ◽  
Spectrum Disorders ◽  
Phenotypic Specificity

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders of genetic and environmental etiologies. Some ASD cases are syndromic: associated with clinically defined patterns of somatic abnormalities and a neurobehavioral phenotype (e.g., Fragile X syndrome). Many cases, however, are idiopathic or non-syndromic. Such disorders present themselves during the early postnatal period when language, speech, and personality start to develop. ASDs manifest by deficits in social communication and interaction, restricted and repetitive patterns of behavior across multiple contexts, sensory abnormalities across multiple modalities and comorbidities, such as epilepsy among many others. ASDs are disorders of connectivity, as synaptic dysfunction is common to both syndromic and idiopathic forms. While multiple theories have been proposed, particularly in idiopathic ASDs, none address why certain brain areas (e.g., frontotemporal) appear more vulnerable than others or identify factors that may affect phenotypic specificity. In this hypothesis article, we identify possible routes leading to, and the consequences of, altered connectivity and review the evidence of central and peripheral synaptic dysfunction in ASDs. We postulate that phenotypic specificity could arise from aberrant experience-dependent plasticity mechanisms in frontal brain areas and peripheral sensory networks and propose why the vulnerability of these areas could be part of a model to unify preexisting pathophysiological theories.

scholarly journals Comparing synaptic proteomes across seven mouse models for autism reveals molecular subtypes and deficits in Rho GTPase signaling

2021 ◽  
Author(s):  
Abigail U. Carbonell ◽  
Carmen Freire-Cobo ◽  
Ilana V. Deyneko ◽  
Hediye Erdjument-Bromage ◽  
Amy E. Clipperton-Allen ◽  
...  
Keyword(s):  
Animal Models ◽  
Mouse Models ◽  
Rho Gtpase ◽  
Molecular Subtypes ◽  
Focal Epilepsy ◽  
Fragile X ◽  
Autism Spectrum ◽  
Small Gtpase ◽  
Synaptic Function ◽  
Epilepsy Syndrome

AbstractImpaired synaptic function is a common phenotype in animal models for autism spectrum disorder (ASD), and ASD risk genes are enriched for synaptic function. Here we leverage the availability of multiple ASD mouse models exhibiting synaptic deficits and behavioral correlates of ASD and use quantitative mass spectrometry with isobaric tandem mass tagging (TMT) to compare the hippocampal synaptic proteomes from 7 mouse models. We identified common altered cellular and molecular pathways at the synapse, including changes in Rho family small GTPase signaling, suggesting that it may be a point of convergence in ASD. Comparative analyses also revealed clusters of synaptic profiles, with similarities observed among models for Fragile X syndrome (Fmr1 knockout), PTEN hamartoma tumor syndrome (Pten haploinsufficiency), and the BTBR+ model of idiopathic ASD. Opposing changes were found in models for cortical dysplasia focal epilepsy syndrome (Cntnap2 knockout), Phelan McDermid syndrome (Shank3 InsG3680), Timothy syndrome (Cacna1c G406R), and ANKS1B syndrome (Anks1b haploinsufficiency), which were similar to each other. We propose that these clusters of synaptic profiles form the basis for molecular subtypes that explain genetic heterogeneity in ASD despite a common clinical diagnosis. Drawn from an internally controlled survey of the synaptic proteome across animal models, our findings support the notion that synaptic dysfunction in the hippocampus is a shared mechanism of disease in ASD, and that Rho GTPase signaling may be an important pathway leading to disease phenotypes in autism.

scholarly journals The organization and developmental establishment of cortical interneuron presynaptic circuits

2020 ◽  
Author(s):  
Gabrielle Pouchelon ◽  
Yannick Bollmann ◽  
Elaine Fisher ◽  
Chimuanya K Agba ◽  
Qing Xu ◽  
...  
Keyword(s):  
Fragile X ◽  
Inhibitory Interneurons ◽  
Loss Of Function ◽  
Cortical Circuits ◽  
Cell Type ◽  
Cortical Interneuron ◽  
First Order ◽  
Cortical Areas ◽  
Cell Type Specific ◽  
Do So

Sensory and cognitive functions are processed in discrete cortical areas and depend upon the integration of long range cortical and subcortical inputs. PV and SST inhibitory interneurons (cINs) gate these inputs and failure to do so properly is implicated in many neurodevelopmental disorders. The logic by which these interneuron populations are integrated into cortical circuits and how these vary across sensory versus associative cortical areas is unknown. To answer this question, we began by surveying the breadth of afferents impinging upon PV and SST cINs within distinct cortical areas. We found that presynaptic inputs to both cIN populations are similar and primarily dictated by their areal location. By contrast, the timing of when they receive these afferents is cell-type specific. In sensory regions, both SST and PV cINs initially receive thalamocortical first order inputs. While by adulthood PV cINs remain heavily skewed towards first order inputs, SST cINs receive an equal balance of first and higher order thalamic afferents. Remarkably, while perturbations to sensory experience affect PV cIN thalamocortical connectivity, SST cIN connectivity is disrupted in a model of fragile X syndrome (Fmr1 loss of function) but not a model of ASD (Shank3B loss of function). Altogether, these data provide a comprehensive map of cIN afferents within different functional cortical areas and reveal the region-specific logic by which PV and SST cIN circuits are established.

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