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 Rho GTPase Regulators and Effectors in Autism Spectrum Disorders: Animal Models and Insights for Therapeutics

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 835 ◽  
Author(s):  
Daji Guo ◽  
Xiaoman Yang ◽  
Lei Shi
Keyword(s):  
Animal Models ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Autism Spectrum ◽  
Neuronal Morphology ◽  
Nucleotide Exchange ◽  
Cellular Processes ◽  
Research Initiative ◽  
Genes Encoding ◽  
And Function

The Rho family GTPases are small G proteins that act as molecular switches shuttling between active and inactive forms. Rho GTPases are regulated by two classes of regulatory proteins, guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Rho GTPases transduce the upstream signals to downstream effectors, thus regulating diverse cellular processes, such as growth, migration, adhesion, and differentiation. In particular, Rho GTPases play essential roles in regulating neuronal morphology and function. Recent evidence suggests that dysfunction of Rho GTPase signaling contributes substantially to the pathogenesis of autism spectrum disorder (ASD). It has been found that 20 genes encoding Rho GTPase regulators and effectors are listed as ASD risk genes by Simons foundation autism research initiative (SFARI). This review summarizes the clinical evidence, protein structure, and protein expression pattern of these 20 genes. Moreover, ASD-related behavioral phenotypes in animal models of these genes are reviewed, and the therapeutic approaches that show successful treatment effects in these animal models are discussed.

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 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 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 Overview of current mouse models of autism and strategies for their development using CRISPR/Cas9 technology

2018 ◽  
Vol 112 (1) ◽  
pp. 19
Author(s):  
Anja DOMADENIK
Keyword(s):  
Animal Models ◽  
Mouse Models ◽  
Genome Engineering ◽  
New Technologies ◽  
Current Knowledge ◽  
Autism Spectrum ◽  
Phenotypic Traits ◽  
Knock Out ◽  
Sgrna Design ◽  
Spectrum Disorders

<p>Autism spectrum disorders (ASD) are a group of highly heterogenous neurological disorders that are believed to have strong genetic component. Due to the limited use of approaches of functional genomics in human medicine, creating adequate animal models for the study of complex human diseases shows great potential. There are several already established mouse models of autism that offer insight into single phenotypic traits, although causes for its complex phenotype have not yet been fully understood. Development of new technologies, such as CRISPR/Cas9, represent great capability for targeted genome engineering and establishment of new animal models. This article provides an up to date overview of current knowledge in the area of autism genomics and describes the potential of CRISPR/Cas9 technology for the establishment of new mouse models, representing sgRNA design as one of the initial steps in planning a CRISPR/Cas9 single knock-out experiment. In addition, it offers an overview of current approaches to behavioural studies, explaining how relevant animal models could be developed.</p>

Clinical and Genetic Profile of Autism Spectrum Disorder–Epilepsy (ASD-E) Phenotype: Two Sides of the Same Coin!

2020 ◽  
Vol 51 (6) ◽  
pp. 390-398 ◽  
Author(s):  
Sudhakar Karunakaran ◽  
Ramshekhar N. Menon ◽  
Sruthi S. Nair ◽  
S. Santhakumar ◽  
Muralidharan Nair ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Age Of Onset ◽  
Focal Epilepsy ◽  
Diagnostic Yield ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Chromosomal Microarray ◽  
Seizure Type ◽  
Epilepsy Syndrome ◽  
Genetic Profile

The clinical phenotype of autism spectrum disorder and epilepsy (ASD-E) is a common neurological presentation in various genetic disorders, irrespective of the underlying pathophysiological mechanisms. Here we describe the demographic and clinical profiles, coexistent neurological conditions, type of seizures, epilepsy syndrome, and EEG findings in 11 patients with ASD-E phenotype with proven genetic etiology. The commonest genetic abnormality noted was CDKL5 mutation (3), MECP2 mutation (2), and 1p36 deletion (2). The median age of onset of clinical seizures was 6 months (range, 10 days to 11 years). The most common seizure type was focal onset seizures with impaired awareness, observed in 7 (63.6%) patients followed by epileptic spasms in 4 (30.8%), generalized tonic-clonic and atonic seizures in 3 (27.3%) patients each and tonic seizures in 2 (18.2%) patients and myoclonic seizures in 1 (9.1%) patient. Focal and multifocal interictal epileptiform abnormalities were seen in 6 (54.6%) and 5 (45.5%) patients, respectively. Epileptic encephalopathy and focal epilepsy were seen in 7 (63.6%) and 4 (36.4%) patients, respectively. The diagnostic yield of genetic testing was 44% (11 of 25 patients) and when variants of unknown significance and metabolic defects were included, the yield increased to 60% (15 of 25 patients). We conclude that in patients with ASD-E phenotype with an underlying genetic basis, the clinical seizure type, epilepsy syndrome, and EEG patterns are variable. Next-generation exome sequencing and chromosomal microarray need to be considered in clinical practice as part of evaluation of children with ASD-E phenotype.

Neuronal Hyperexcitability in APPSWE/PS1dE9 Mouse Models of Alzheimer’s Disease

2021 ◽  
pp. 1-15
Author(s):  
Luisa Müller ◽  
Timo Kirschstein ◽  
Rüdiger Köhling ◽  
Angela Kuhla ◽  
Stefan Teipel
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Mouse Models ◽  
Amyloid Β ◽  
Synaptic Function ◽  
Neuronal Firing ◽  
Neuronal Dysfunction ◽  
Neuronal Function ◽  
Neuronal Hyperexcitability

Transgenic mouse models serve a better understanding of Alzheimer’s disease (AD) pathogenesis and its consequences on neuronal function. Well-known and broadly used AD models are APPswe/PS1dE9 mice, which are able to reproduce features of amyloid-β (Aβ) plaque formations as well as neuronal dysfunction as reflected in electrophysiological recordings of neuronal hyperexcitability. The most prominent findings include abnormal synaptic function and synaptic reorganization as well as changes in membrane threshold and spontaneous neuronal firing activities leading to generalized excitation-inhibition imbalances in larger neuronal circuits and networks. Importantly, these findings in APPswe/PS1dE9 mice are at least partly consistent with results of electrophysiological studies in humans with sporadic AD. This underscores the potential to transfer mechanistic insights into amyloid related neuronal dysfunction from animal models to humans. This is of high relevance for targeted downstream interventions into neuronal hyperexcitability, for example based on repurposing of existing antiepileptic drugs, as well as the use of combinations of imaging and electrophysiological readouts to monitor effects of upstream interventions into amyloid build-up and processing on neuronal function in animal models and human studies. This article gives an overview on the pathogenic and methodological basis for recording of neuronal hyperexcitability in AD mouse models and on key findings in APPswe/PS1dE9 mice. We point at several instances to the translational perspective into clinical intervention and observation studies in humans. We particularly focus on bi-directional relations between hyperexcitability and cerebral amyloidosis, including build-up as well as clearance of amyloid, possibly related to sleep and so called glymphatic system function.

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&rsquo;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 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.

Sign in / Sign up

Export Citation Format

Share Document