scholarly journals Social behavioral deficits in NF1 emerge from peripheral chemosensory neuron dysfunction

2019 ◽  
Author(s):  
Emilia H. Moscato ◽  
Christine Dubowy ◽  
James A. Walker ◽  
Matthew S. Kayser
Keyword(s):  
Neuronal Activity ◽  
Neurodevelopmental Disorder ◽  
Social Behaviors ◽  
Neurofibromatosis Type ◽  
Ras Signaling ◽  
Social Deficits ◽  
Behavioral Deficits ◽  
Sustained Effect ◽  
Chemosensory Neuron ◽  
Peripheral Sensory

AbstractNeurofibromatosis type 1 (NF1) is a neurodevelopmental disorder commonly associated with social and communicative disabilities. The cellular and circuit mechanisms by which loss of neurofibromin 1 (Nf1) function results in social deficits are unknown. Here, we identify social behavioral dysregulation with loss of Nf1 in Drosophila. These deficits map to primary dysfunction of a small group of peripheral sensory neurons, rather than central brain circuits. Specifically, Nf1 regulation of Ras signaling in adult, Ppk23+ chemosensory cells is required for normal social behaviors in flies. Loss of Nf1 results in attenuated ppk23+ neuronal activity in response to pheromonal cues, and circuit-specific manipulation of Nf1 expression or neuronal activity in ppk23+ neurons rescues social deficits. Unexpectedly, this disrupted sensory processing gives rise to persistent changes in behavior lasting beyond the social interaction, indicating a sustained effect of an acute sensory misperception. Together our data identify a specific circuit mechanism through which Nf1 acts to regulate social behaviors, and suggest social deficits in NF1 arise from propagation of sensory misinformation.

scholarly journals Modulation of cAMP and Ras Signaling Pathways Improves Distinct Behavioral Deficits in a Zebrafish Model of Neurofibromatosis Type 1

Cell Reports ◽  
2014 ◽  
Vol 8 (5) ◽  
pp. 1265-1270 ◽  
Author(s):  
Marc A. Wolman ◽  
Eric D. de Groh ◽  
Sean M. McBride ◽  
Thomas A. Jongens ◽  
Michael Granato ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Ras Signaling ◽  
Zebrafish Model ◽  
Behavioral Deficits

scholarly journals Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kohei Kitagawa ◽  
Kensuke Matsumura ◽  
Masayuki Baba ◽  
Momoka Kondo ◽  
Tomoya Takemoto ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Model ◽  
Mouse Models ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutation ◽  
Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

scholarly journals Distinctive epigenomic alterations in NF1-deficient cutaneous and plexiform neurofibromas drive differential MKK/p38 signaling

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jamie L. Grit ◽  
Benjamin K. Johnson ◽  
Patrick S. Dischinger ◽  
Curt J. Essenburg ◽  
Marie Adams ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Transcriptome Profiling ◽  
Neurofibromatosis Type ◽  
Mapk Signaling ◽  
Ras Signaling ◽  
Methylation Array ◽  
Clinical Behavior ◽  
Plexiform Neurofibromas ◽  
Cellular Processes ◽  
Peripheral Nerve Sheath Tumors

AbstractBenign peripheral nerve sheath tumors are the clinical hallmark of Neurofibromatosis Type 1. They account for substantial morbidity and mortality in NF1. Cutaneous (CNF) and plexiform neurofibromas (PNF) share nearly identical histology, but maintain different growth rates and risk of malignant conversion. The reasons for this disparate clinical behavior are not well explained by recent genome or transcriptome profiling studies. We hypothesized that CNFs and PNFs are epigenetically distinct tumor types that exhibit differential signaling due to genome-wide and site-specific methylation events. We interrogated the methylation profiles of 45 CNFs and 17 PNFs from NF1 subjects with the Illumina EPIC 850K methylation array. Based on these profiles, we confirm that CNFs and PNFs are epigenetically distinct tumors with broad differences in higher-order chromatin states and specific methylation events altering genes involved in key biological and cellular processes, such as inflammation, RAS/MAPK signaling, actin cytoskeleton rearrangement, and oxytocin signaling. Based on our identification of two separate DMRs associated with alternative leading exons in MAP2K3, we demonstrate differential RAS/MKK3/p38 signaling between CNFs and PNFs. Epigenetic reinforcement of RAS/MKK/p38 was a defining characteristic of CNFs leading to pro-inflammatory signaling and chromatin conformational changes, whereas PNFs signaled predominantly through RAS/MEK. Tumor size also correlated with specific CpG methylation events. Taken together, these findings confirm that NF1 deficiency influences the epigenetic regulation of RAS signaling fates, accounting for observed differences in CNF and PNF clinical behavior. The extension of these findings is that CNFs may respond differently than PNFs to RAS-targeted therapeutics raising the possibility of targeting p38-mediated inflammation for CNF treatment.

scholarly journals Affinity Purification of NF1 Protein–Protein Interactors Identifies Keratins and Neurofibromin Itself as Binding Partners

Genes ◽  
2019 ◽  
Vol 10 (9) ◽  
pp. 650 ◽  
Author(s):  
Rachel M. Carnes ◽  
Robert A. Kesterson ◽  
Bruce R. Korf ◽  
James A. Mobley ◽  
Deeann Wallis
Keyword(s):  
Protein Interactions ◽  
Drug Targets ◽  
Affinity Purification ◽  
Neurofibromatosis Type ◽  
Hek293 Cells ◽  
Ras Signaling ◽  
Affinity Tag ◽  
Pathogenic Variants ◽  
Binding Partners ◽  
Keratin Expression

Neurofibromatosis Type 1 (NF1) is caused by pathogenic variants in the NF1 gene encoding neurofibromin. Definition of NF1 protein–protein interactions (PPIs) has been difficult and lacks replication, making it challenging to define binding partners that modulate its function. We created a novel tandem affinity purification (TAP) tag cloned in frame to the 3’ end of the full-length murine Nf1 cDNA (mNf1). We show that this cDNA is functional and expresses neurofibromin, His-Tag, and can correct p-ERK/ERK ratios in NF1 null HEK293 cells. We used this affinity tag to purify binding partners with Strep-Tactin®XT beads and subsequently, identified them via mass spectrometry (MS). We found the tagged mNf1 can affinity purify human neurofibromin and vice versa, indicating that neurofibromin oligomerizes. We identify 21 additional proteins with high confidence of interaction with neurofibromin. After Metacore network analysis of these 21 proteins, eight appear within the same network, primarily keratins regulated by estrogen receptors. Previously, we have shown that neurofibromin levels negatively regulate keratin expression. Here, we show through pharmacological inhibition that this is independent of Ras signaling, as the inhibitors, selumetinib and rapamycin, do not alter keratin expression. Further characterization of neurofibromin oligomerization and binding partners could aid in discovering new neurofibromin functions outside of Ras regulation, leading to novel drug targets.

scholarly journals Verapamil/Curcumin treatment attenuates the behavioral alterations observed in Williams Syndrome mice by regulation of MAPK pathway and Microglia overexpression

2021 ◽  
Author(s):  
Paula Ortiz-Romero ◽  
Gustavo Egea ◽  
Luis A Pérez-Jurado ◽  
Victoria Campuzano
Keyword(s):  
Mapk Pathway ◽  
Neurodevelopmental Disorder ◽  
Underlying Mechanism ◽  
Brain Regions ◽  
Mapk Signaling ◽  
Potential Candidate ◽  
Neuroprotective Effects ◽  
Behavioral Deficits ◽  
Activated Microglia ◽  
Beneficial Effects

AbstractWilliams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by a distinctive cognitive phenotype for which there currently are not any effective treatments. We investigated the progression of behavioral deficits present in CD (complete deletion) mice, a rodent model of WBS, after chronic treatment with curcumin, verapamil and a combination of both. These compounds have been proven to have beneficial effects over different cognitive aspects of various murine models and thus, may have neuroprotective effects in WBS. Treatment was administered orally dissolved in drinking water. A set of behavioral tests demonstrated the efficiency of combinatorial treatment. Some histological and molecular analyses were performed to analyze the effects of treatment and its underlying mechanism in CD mice. Behavioral improvement correlates with the molecular recovery of several affected pathways regarding MAPK signaling, in tight relation with the control of synaptic transmission. Moreover, CD mice showed an increased activated microglia density in different brain regions, which was prevented by treatment. Therefore, results show that treatment prevented behavioral deficits by recovering altered gene expression in cortex of CD mice, reducing activated microglia and normalizing Bdnf expression levels. These findings unravel the mechanisms underlying the beneficial effects of this novel treatment on behavioral deficits observed in CD mice, and suggest that the combination of curcumin and verapamil could be a potential candidate to treat the cognitive impairments in WBS patients.

Behavioral deficits in left hemispatial neglect are related to a reduction of spontaneous neuronal activity in the right superior parietal lobule

2020 ◽  
Vol 138 ◽  
pp. 107356
Author(s):  
Björn Machner ◽  
Janina von der Gablentz ◽  
Martin Göttlich ◽  
Wolfgang Heide ◽  
Christoph Helmchen ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Hemispatial Neglect ◽  
Superior Parietal Lobule ◽  
Behavioral Deficits ◽  
Spontaneous Neuronal Activity ◽  
Parietal Lobule ◽  
The Right

scholarly journals Co-Treatment With Verapamil and Curcumin Attenuates the Behavioral Alterations Observed in Williams–Beuren Syndrome Mice by Regulation of MAPK Pathway and Microglia Overexpression

2021 ◽  
Vol 12 ◽  
Author(s):  
Paula Ortiz-Romero ◽  
Alejandro González-Simón ◽  
Gustavo Egea ◽  
Luis A. Pérez-Jurado ◽  
Victoria Campuzano
Keyword(s):  
Mapk Pathway ◽  
Neurodevelopmental Disorder ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Potential Candidate ◽  
Behavioral Alterations ◽  
Neuroprotective Effects ◽  
Behavioral Deficits ◽  
Activated Microglia ◽  
Beneficial Effects

Williams–Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by a distinctive cognitive phenotype for which there are currently no effective treatments. We investigated the progression of behavioral deficits present in WBS complete deletion (CD) mice, after chronic treatment with curcumin, verapamil, and a combination of both. These compounds have been proven to have beneficial effects over different cognitive aspects of various murine models and, thus, may have neuroprotective effects in WBS. Treatment was administered orally dissolved in drinking water. A set of behavioral tests demonstrated the efficiency of combinatorial treatment. Some histological and molecular analyses were performed to analyze the effects of treatment and its underlying mechanism. CD mice showed an increased density of activated microglia in the motor cortex and CA1 hippocampal region, which was prevented by co-treatment. Behavioral improvement correlated with the molecular recovery of several affected pathways regarding MAPK signaling, in tight relation to the control of synaptic transmission, and inflammation. Therefore, the results show that co-treatment prevented behavioral deficits by recovering altered gene expression in the cortex of CD mice and reducing activated microglia. These findings unravel the mechanisms underlying the beneficial effects of this novel treatment on behavioral deficits observed in CD mice and suggest that the combination of curcumin and verapamil could be a potential candidate to treat the cognitive impairments in WBS patients.

scholarly journals An autism-associated mutation in salt inducible kinase 1 causes repetitive behavior and social deficits due to enhanced excitatory neuronal functions in mice.

2021 ◽  
Author(s):  
Moataz Badawi ◽  
Takuma Mori ◽  
Taiga Kurihara ◽  
Takahiro Yoshizawa ◽  
Katsuhiro Nohara ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Subcellular Distribution ◽  
Repetitive Behavior ◽  
Epileptic Encephalopathy ◽  
Excitatory Synaptic Transmission ◽  
Electrophysiological Recording ◽  
Social Deficits ◽  
Behavioral Deficits ◽  
Neural Excitability ◽  
Neuronal Functions

Abstract Background:Six mutations in the salt inducible kinase 1 (SIK1) coding gene have been identified in the early infantile epileptic encephalopathy (EIEE-30) patients accompanied by autistic symptoms, such as repetitive behavior and social behavioral deficits. Among these mutations, two are nonsense mutations that truncate the C-terminal region. It has been shown that the C-terminal truncated form of SIK1 protein affects the subcellular distribution of SIK1 protein, tempting to speculate the relevance to the pathophysiology of the disorders.Methods:We generated SIK1 mutant (SIK1-MT) mice recapitulating the C-terminal truncated mutations using CRISPR/Cas9-mediated genome editing. We performed cellular assays to examine the subcellular localization of SIK1-MT. We also performed patch clamp electrophysiological recording and behavioral tests to evaluate the neuronal functions and behaviors in SIK1-MT mice. Pharmacological experiments using risperidone were also performed to examine the potential therapeutics of the disorder.Results:SIK1-MT protein was distributed in the nucleus and cytoplasm, whereas the distribution of wild-type SIK1 was restricted to the nucleus. We found the disruption of excitatory and inhibitory (E/I) synaptic balance due to an increase in excitatory synaptic transmission and enhancement of neural excitability in the pyramidal neurons in layer 5 of the medial prefrontal cortex in SIK1-MT mice. We also found the increased repetitive behavior and social behavioral deficits in SIK1-MT mice. The risperidone administration attenuated the neural excitability and excitatory synaptic transmission, but the disrupted E/I synaptic balance was unchanged because it also reduced the inhibitory synaptic transmission. Risperidone also eliminated the repetitive behavior, but not social behavioral deficits.Limitations:We failed to identify drugs that can cure the social behavioral deficits in this mouse model.Conclusions:In the present study, we generated model mice for EIEE-30 recapitulating C-terminal truncated SIK1 mutation discovered in human patients. We found that the C-terminal deletion of SIK1 affects the subcellular distribution of SIK1, resulting in the elevated excitability of neuronal networks and autistic behaviors in the mutant mice. Repetitive behavior, but not social deficits, was restored by risperidone, probably due to the decrease of both excitatory and inhibitory synaptic functions by the drug.

scholarly journals Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome

2021 ◽  
Author(s):  
Elizabeth Berg ◽  
Stela Petkova ◽  
Heather A Born ◽  
Anna Adhikari ◽  
Anne E Anderson ◽  
...  
Keyword(s):  
Growth Factor ◽  
Angelman Syndrome ◽  
Motor Behavior ◽  
Neurodevelopmental Disorder ◽  
Model Systems ◽  
Seizure Threshold ◽  
Insulin Like Growth Factor ◽  
Behavioral Deficits ◽  
Rat Models

Background: Angelman Syndrome (AS) is a rare neurodevelopmental disorder for which there is currently no cure or effective therapeutic. Since the genetic cause of AS is known to be dysfunctional expression of the maternal allele of ubiquitin protein ligase E3A (UBE3A), several genetic animal models of AS have been developed. Both the Ube3a maternal deletion mouse and rat models of AS reliably demonstrate behavioral phenotypes of relevance to AS and therefore offer suitable in vivo systems in which to test potential therapeutics. One promising candidate treatment is insulin-like growth factor-2 (IGF-2), which has recently been shown to ameliorate behavioral deficits in the mouse model of AS and improve cognitive abilities across model systems. Methods: We used both the Ube3a maternal deletion mouse and rat models of AS to evaluate the ability of IGF-2 to improve electrophysiological and behavioral outcomes. Results: Acute systemic administration of IGF-2 had an effect on electrophysiological activity in the brain and on a metric of motor ability, however the effects were not enduring or extensive. Additional metrics of motor behavior, learning, ambulation, and coordination were unaffected and IGF-2 did not improve social communication, seizure threshold, or cognition. Limitations: The generalizability of these results to humans is difficult to predict and it remains possible that dosing schemes (i.e., chronic or subchronic dosing), routes, and/or post-treatment intervals other than that used herein may show more efficacy. Conclusions: Despite a few observed effects of IGF-2, our results taken together indicate that IGF-2 treatment does not profoundly improve behavioral deficits in mice or rat models of AS. These findings shed cautionary light on the potential utility of acute systemic IGF-2 administration in the treatment of AS.

scholarly journals Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gabrielle L. Sell ◽  
Wendy Xin ◽  
Emily K. Cook ◽  
Mark A. Zbinden ◽  
Thomas B. Schaffer ◽  
...  
Keyword(s):  
Angelman Syndrome ◽  
Developmental Disorders ◽  
Motor Coordination ◽  
Synapse Formation ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Behavioral Deficits ◽  
Altered Expression ◽  
Exciting Potential

AbstractIn humans, loss-of-function mutations in the UBE3A gene lead to the neurodevelopmental disorder Angelman syndrome (AS). AS patients have severe impairments in speech, learning and memory, and motor coordination, for which there is currently no treatment. In addition, UBE3A is duplicated in > 1–2% of patients with autism spectrum disorders—a further indication of the significant role it plays in brain development. Altered expression of UBE3A, an E3 ubiquitin ligase, is hypothesized to lead to impaired levels of its target proteins, but identifying the contribution of individual UBE3A targets to UBE3A-dependent deficits remains of critical importance. Ephexin5 is a putative UBE3A substrate that has restricted expression early in development, regulates synapse formation during hippocampal development, and is abnormally elevated in AS mice, modeled by maternally-derived Ube3a gene deletion. Here, we report that Ephexin5 can be directly ubiquitylated by UBE3A. Furthermore, removing Ephexin5 from AS mice specifically rescued hippocampus-dependent behaviors, CA1 physiology, and deficits in dendritic spine number. Our findings identify Ephexin5 as a key driver of hippocampal dysfunction and related behavioral deficits in AS mouse models. These results demonstrate the exciting potential of targeting Ephexin5, and possibly other UBE3A substrates, to improve symptoms of AS and other UBE3A-related developmental disorders.

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