Transient Enhanced GluA2 Expression in Young Hippocampal Neurons of a Fragile X Mouse Model

AMPA-type glutamate receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits and play important roles in synaptic transmission and plasticity. Here, we have investigated the development of AMPAR-mediated synaptic transmission in the hippocampus of the Fmr1 knock-out (KO) mouse, a widely used model of Fragile X syndrome (FXS). FXS is the leading monogenic cause of intellectual disability and autism spectrum disorders (ASD) and it is considered a neurodevelopmental disorder. For that reason, we investigated synaptic properties and dendritic development in animals from an early stage when synapses are starting to form up to adulthood. We found that hippocampal CA1 pyramidal neurons in the Fmr1-KO mouse exhibit a higher AMPAR-NMDAR ratio early in development but reverses to normal values after P13. This increase was accompanied by a larger presence of the GluA2-subunit in synaptic AMPARs that will lead to altered Ca2+ permeability of AMPARs that could have a profound impact upon neural circuits, learning, and diseases. Following this, we found that young KO animals lack Long-term potentiation (LTP), a well-understood model of synaptic plasticity necessary for proper development of circuits, and exhibit an increased frequency of spontaneous miniature excitatory postsynaptic currents, a measure of synaptic density. Furthermore, post hoc morphological analysis of recorded neurons revealed altered dendritic branching in the KO group. Interestingly, all these anomalies are transitory and revert to normal values in older animals. Our data suggest that loss of FMRP during early development leads to temporary upregulation of the GluA2 subunit and this impacts synaptic plasticity and altering morphological dendritic branching.

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SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice

10.1101/2021.01.24.427868 ◽

2021 ◽

Author(s):

Kan Yang ◽

Yuhan Shi ◽

Xiujuan Du ◽

Yuefang Zhang ◽

Shifang Shan ◽

...

Keyword(s):

Social Interaction ◽

De Novo ◽

Fragile X ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Genetic Components ◽

Truncating Mutation ◽

Synaptic Functions ◽

Core Symptoms

AbstractAutism spectrum disorder (ASD) is a highly heritable complex neurodevelopmental disorder. While the core symptoms of ASD are defects of social interaction and repetitive behaviors, over 50% of ASD patients have comorbidity of intellectual disabilities (ID) or developmental delay (DD), raising the question whether there are genetic components and neural circuits specific for core symptoms of ASD. Here, by focusing on ASD patients who do not show compound ID or DD, we identified a de novo heterozygous gene-truncating mutation of the Sentrin-specific peptidase1 (SENP1) gene, coding the small ubiquitin-like modifiers (SUMO) deconjugating enzyme, as a potentially new candidate gene for ASD. We found that Senp1 haploinsufficient mice exhibited core symptoms of autism such as deficits in social interaction and repetitive behaviors, but normal learning and memory ability. Moreover, we found that the inhibitory and excitatory synaptic functions were severely affected in the retrosplenial agranular (RSA) cortex of Senp1 haploinsufficient mice. Lack of Senp1 led to over SUMOylation and degradation of fragile X mental retardation protein (FMRP) proteins, which is coded by the FMR1 gene, also implicated in syndromic autism. Importantly, re-introducing SENP1 or FMRP specifically in RSA fully rescued the defects of synaptic functions and core autistic-like symptoms of Senp1 haploinsufficient mice. Taken together, these results elucidate that disruption of the SENP1-FMRP regulatory axis in the RSA may cause core autistic symptoms, which further provide a candidate brain region for therapeutic intervene of ASD by neural modulation approaches.

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Age-Related Cognitive Impairment: Role of Reduced Synaptobrevin-2 Levels in Deficits of Memory and Synaptic Plasticity

The Journals of Gerontology Series A ◽

10.1093/gerona/glz013 ◽

2019 ◽

Vol 75 (9) ◽

pp. 1624-1632 ◽

Cited By ~ 3

Author(s):

Albert Orock ◽

Sreemathi Logan ◽

Ferenc Deak

Keyword(s):

Cognitive Impairment ◽

Synaptic Plasticity ◽

Learning And Memory ◽

Hippocampal Neurons ◽

Long Term Potentiation ◽

Receptor Protein ◽

Protein Levels ◽

Ca1 Region ◽

Age Related ◽

Term Potentiation

AbstractCognitive impairment in the aging population is quickly becoming a health care priority, for which currently no disease-modifying treatment is available. Multiple domains of cognition decline with age even in the absence of neurodegenerative diseases. The cellular and molecular changes leading to cognitive decline with age remain elusive. Synaptobrevin-2 (Syb2), the major vesicular SNAP receptor protein, highly expressed in the cerebral cortex and hippocampus, is essential for synaptic transmission. We have analyzed Syb2 protein levels in mice and found a decrease with age. To investigate the functional consequences of lower Syb2 expression, we have used adult Syb2 heterozygous mice (Syb2+/−) with reduced Syb2 levels. This allowed us to mimic the age-related decrease of Syb2 in the brain in order to selectively test its effects on learning and memory. Our results show that Syb2+/− animals have impaired learning and memory skills and they perform worse with age in the radial arm water maze assay. Syb2+/− hippocampal neurons have reduced synaptic plasticity with reduced release probability and impaired long-term potentiation in the CA1 region. Syb2+/− neurons also have lower vesicular release rates when compared to WT controls. These results indicate that reduced Syb2 expression with age is sufficient to cause cognitive impairment.

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Chemical LTD, but not LTP, induces transient accumulation of gelsolin in dendritic spines

Biological Chemistry ◽

10.1515/hsz-2019-0110 ◽

2019 ◽

Vol 400 (9) ◽

pp. 1129-1139 ◽

Cited By ~ 2

Author(s):

Iryna Hlushchenko ◽

Pirta Hotulainen

Keyword(s):

Synaptic Plasticity ◽

Dendritic Spines ◽

Hippocampal Neurons ◽

Long Term Potentiation ◽

Excitatory Synapses ◽

Signal Molecule ◽

Brain Functions ◽

Dendritic Shaft ◽

Term Potentiation

Abstract Synaptic plasticity underlies central brain functions, such as learning. Ca2+ signaling is involved in both strengthening and weakening of synapses, but it is still unclear how one signal molecule can induce two opposite outcomes. By identifying molecules, which can distinguish between signaling leading to weakening or strengthening, we can improve our understanding of how synaptic plasticity is regulated. Here, we tested gelsolin’s response to the induction of chemical long-term potentiation (cLTP) or long-term depression (cLTD) in cultured rat hippocampal neurons. We show that gelsolin relocates from the dendritic shaft to dendritic spines upon cLTD induction while it did not show any relocalization upon cLTP induction. Dendritic spines are small actin-rich protrusions on dendrites, where LTD/LTP-responsive excitatory synapses are located. We propose that the LTD-induced modest – but relatively long-lasting – elevation of Ca2+ concentration increases the affinity of gelsolin to F-actin. As F-actin is enriched in dendritic spines, it is probable that increased affinity to F-actin induces the relocalization of gelsolin.

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Neurobiology of Autism and Intellectual Disability

10.1093/med/9780199937837.003.0052 ◽

2017 ◽

Author(s):

Dejan B. Budimirovic ◽

Megha Subramanian

Keyword(s):

Fragile X ◽

Neurodevelopmental Disorder ◽

Full Range ◽

Therapeutic Targets ◽

Autism Spectrum ◽

Fmr1 Gene ◽

Health Concern ◽

Complex Disorders ◽

Mglur5 Antagonist ◽

Core Symptoms

Fragile X syndrome (FXS) is a neurodevelopmental disorder that manifests with a range of cognitive, behavioral, and social impairments. It is a monogenetic disease caused by silencing of the FMR1 gene, in contrast to autism spectrum disorder (ASD) that is a behaviorally-defined set of complex disorders. Because ASD is a major and growing public health concern, current research is focused on identifying common therapeutic targets among patients with different molecular etiologies. Due to the prevalence of ASD in FXS and its shared neurophysiology with ASD, FXS has been extensively studied as a model for ASD. Studies in the animal models have provided breakthrough insights into the pathophysiology of FXS that have led to novel therapeutic targets for its core deficits (e.g., mGluR theory of fragile X). Yet recent clinical trials of both GABA-B agonist and mGluR5 antagonist revealed a lack of specific and sensitive outcome measures capturing the full range of improvements of patients with FXS. Recent research shows promise for the mapping of the multitude of genetic variants in ASD onto shared pathways with FXS. Nonetheless, in light of the huge level of locus heterogeneity in ASD, further effort in finding convergence in specific molecular pathways and reliable biomarkers is required in order to perform targeted treatment trials with sufficient sample size. This chapter focuses on the neurobehavioral phenotype caused by a full-mutation of the FMR1 gene, namely FXS, and the neurobiology of this disorder of relevance to the targeted molecular treatments of its core symptoms.

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Hyperexcitability and loss of feedforward inhibition in the Fmr1KO lateral amygdala

10.1101/2020.04.21.053652 ◽

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.

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Neuroligin-3 Regulates Excitatory Synaptic Transmission and EPSP-Spike Coupling in the Dentate Gyrus In Vivo

Molecular Neurobiology ◽

10.1007/s12035-021-02663-9 ◽

2021 ◽

Author(s):

Julia Muellerleile ◽

Matej Vnencak ◽

Angelo Ippolito ◽

Dilja Krueger-Burg ◽

Tassilo Jungenitz ◽

...

Keyword(s):

Synaptic Transmission ◽

Dentate Gyrus ◽

Long Term Potentiation ◽

Autism Spectrum ◽

Perforant Path ◽

Adhesion Protein ◽

Neuronal Excitation ◽

Term Potentiation

Abstract Neuroligin-3 (Nlgn3), a neuronal adhesion protein implicated in autism spectrum disorder (ASD), is expressed at excitatory and inhibitory postsynapses and hence may regulate neuronal excitation/inhibition balance. To test this hypothesis, we recorded field excitatory postsynaptic potentials (fEPSPs) in the dentate gyrus of Nlgn3 knockout (KO) and wild-type mice. Synaptic transmission evoked by perforant path stimulation was reduced in KO mice, but coupling of the fEPSP to the population spike was increased, suggesting a compensatory change in granule cell excitability. These findings closely resemble those in neuroligin-1 (Nlgn1) KO mice and could be partially explained by the reduction in Nlgn1 levels we observed in hippocampal synaptosomes from Nlgn3 KO mice. However, unlike Nlgn1, Nlgn3 is not necessary for long-term potentiation. We conclude that while Nlgn1 and Nlgn3 have distinct functions, both are required for intact synaptic transmission in the mouse dentate gyrus. Our results indicate that interactions between neuroligins may play an important role in regulating synaptic transmission and that ASD-related neuroligin mutations may also affect the synaptic availability of other neuroligins.

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Development of an Autism Screening Classification Model for Toddlers

10.5121/csit.2021.111508 ◽

2021 ◽

Author(s):

Afef Saihi ◽

Hussam Alshraideh

Keyword(s):

Neural Network ◽

Machine Learning ◽

Early Stage ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Therapeutic Interventions ◽

Classification Model ◽

Machine Learning Techniques ◽

Early Screening

Autism spectrum disorder ASD is a neurodevelopmental disorder associated with challenges in communication, social interaction, and repetitive behaviors. Getting a clear diagnosis for a child is necessary for starting early intervention and having access to therapy services. However, there are many barriers that hinder the screening of these kids for autism at an early stage which might delay further the access to therapeutic interventions. One promising direction for improving the efficiency and accuracy of ASD detection in toddlers is the use of machine learning techniques to build classifiers that serve the purpose. This paper contributes to this area and uses the data developed by Dr. Fadi Fayez Thabtah to train and test various machine learning classifiers for the early ASD screening. Based on various attributes, three models have been trained and compared which are Decision tree C4.5, Random Forest, and Neural Network. The three models provided very good accuracies based on testing data, however, it is the Neural Network that outperformed the other two models. This work contributes to the early screening of toddlers by helping identify those who have ASD traits and should pursue formal clinical diagnosis.

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Astrocytes derived from ASD patients alter behavior and destabilize neuronal activity through aberrant Ca2+ signaling

10.1101/2021.10.11.463231 ◽

2021 ◽

Author(s):

Megan Allen ◽

Ben S. Huang ◽

Michael J. Notaras ◽

Aiman Lodhi ◽

Estibaliz Barrio Alonso ◽

...

Keyword(s):

Neuronal Activity ◽

Hippocampal Neurons ◽

Repetitive Behavior ◽

Long Term Potentiation ◽

Autism Spectrum ◽

Network Activity ◽

Postmortem Brain ◽

Primary Role ◽

Neuronal Network Activity ◽

Postmortem Brain Tissue

AbstractThe cellular mechanisms of Autism Spectrum Disorder (ASD) are poorly understood. Cumulative evidence suggests that abnormal synapse function underlies many features of this disease. Astrocytes play in several key neuronal processes, including the formation of synapses and the modulation of synaptic plasticity. Astrocyte abnormalities have also been identified in the postmortem brain tissue of ASD patients. However, it remains unclear whether astrocyte pathology plays a mechanistic role in ASD, as opposed to a compensatory response. To address this, we strategically combined stem cell culturing with transplantation techniques to determine disease specific properties inherent to patient derived astrocytes. We demonstrate that ASD astrocytes induce repetitive behavior as well as impair memory and long-term potentiation when transplanted into the healthy mouse brain. These in vivo phenotypes were accompanied by reduced neuronal network activity and spine density caused by ASD astrocytes in hippocampal neurons in vitro. Transplanted ASD astrocytes also exhibit exaggerated Ca2+ fluctuations in chimeric brains. Genetic modulation of evoked Ca2+ responses in ASD astrocytes modulates behavior and neuronal activity deficits. Thus, we determine that ASD patient astrocytes are sufficient to induce repetitive behavior as well as cognitive deficit, suggesting a previously unrecognized primary role for astrocytes in ASD.

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Disruption of the KH1 domain of Fmr1 leads to transcriptional alterations and attentional deficits in rats

10.1101/338988 ◽

2018 ◽

Cited By ~ 1

Author(s):

Carla E. M. Golden ◽

Michael S. Breen ◽

Lacin Koro ◽

Sankalp Sonar ◽

Kristi Niblo ◽

...

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Rna Binding ◽

Fragile X ◽

Neurodevelopmental Disorder ◽

Point Mutations ◽

Autism Spectrum ◽

Attention Deficits ◽

Hub Genes ◽

Transcriptional Profiles

AbstractFragile X Syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene. FXS is a leading monogenic cause of autism spectrum disorder (ASD) and inherited intellectual disability (ID). In most cases, the mutation is an expansion of a microsatellite (CGG triplet), which leads to suppressed expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein involved in multiple aspects of mRNA metabolism. Interestingly, we found that the previously published Fmr1 knockout rat model of FXS expresses a transcript with an in-frame deletion of a K-homology (KH) domain, KH1. KH domains are RNA-binding domains of FMR1 and several of the few, known point mutations associated with FXS are found within them. We observed that this deletion leads to medial prefrontal cortex (mPFC)-dependent attention deficits, similar to those observed in FXS, and to alterations in transcriptional profiles within the mPFC, which mapped to two weighted gene coexpression network analysis modules. We demonstrated that these modules are conserved in human frontal cortex, are enriched for known FMRP targets and for genes involved in neuronal and synaptic processes, and that one is enriched for genes that are implicated in ASD, ID, and schizophrenia. Hub genes in these conserved modules represent potential targets for FXS. These findings provide support for a prefrontal deficit in FXS, indicate that attentional testing might be a reliable cross-species tool for investigating the pathophysiology of FXS and a potential readout for pharmacotherapy testing, and identify dysregulated gene expression modules in a relevant brain region.Significance StatementThe significance of the current study lies in two key domains. First, this study demonstrates that deletion of the Fmrp-KH1 domain is sufficient to cause major mPFC-dependent attention deficits in both males and females, like those observed in both individuals with FXS and in knockout mouse models for FXS. Second, the study shows that deletion of the KH1 domain leads to alterations in the transcriptional profiles within the medial prefrontal cortex (mPFC), which are of potential translational value for subjects with FXS. These findings indicate that attentional testing might be a reliable cross-species tool for investigating the pathophysiology of FXS and a potential readout for pharmacotherapy testing and also highlight hub genes for follow up.

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CAP2 is a novel regulator of Cofilin in synaptic plasticity and Alzheimer’s disease

10.1101/789552 ◽

2019 ◽

Author(s):

Silvia Pelucchi ◽

Lina Vandermeulen ◽

Lara Pizzamiglio ◽

Bahar Aksan ◽

Jing Yan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Synaptic Transmission ◽

Long Term Potentiation ◽

Actin Dynamics ◽

Term Potentiation ◽

Actin Turnover ◽

Normal Spine

AbstractCofilin is one of the major regulators of actin dynamics in spines where it is required for structural synaptic plasticity. However, our knowledge of the mechanisms controlling Cofilin activity in spines remains still fragmented. Here, we describe the cyclase-associated protein 2 (CAP2) as a novel master regulator of Cofilin localization in spines. The formation of CAP2 dimers through its Cys32 is important for CAP2 binding to Cofilin and for normal spine actin turnover. The Cys32-dependent CAP2 homodimerization and association to Cofilin are triggered by long-term potentiation (LTP) and are required for LTP-induced Cofilin translocation into spines, spine remodeling and the potentiation of synaptic transmission. This mechanism is specifically affected in the hippocampus, but not in the superior frontal gyrus, of both Alzheimer’s Disease (AD) patients and APP/PS1 mice, where CAP2 is down-regulated and CAP2 dimer synaptic levels are reduced. In AD hippocampi, Cofilin preferentially associates with CAP2 monomer and is aberrantly localized in spines. Taken together, these results provide novel insights into structural plasticity mechanisms that are defective in AD.

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