scholarly journals STXBP5/tomosyn regulates the small RhoA GTPase to control the dendritic stability of neurons and the surface expression of AMPA receptors

2019 ◽  
Author(s):  
Wenjuan Shen ◽  
Michaela B.C. Kilander ◽  
Morgan S. Bridi ◽  
Jeannine A. Frei ◽  
Robert F. Niescier ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Ampa Receptors ◽  
Surface Expression ◽  
Autism Spectrum ◽  
Dendritic Morphology ◽  
Dendritic Arborization ◽  
Neuronal Morphology ◽  
Rhoa Gtpase ◽  
Wd40 Domain

AbstractTomosyn, a protein encoded by syntaxin-1-binding protein 5 (STXBP5) gene, has a well-established presynaptic role in the inhibition of neurotransmitter release and the reduction of synaptic transmission by its conical interaction with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) machinery. The postsynaptic role of tomosyn in dendritic arborization, spine stability, and trafficking of ionotropic glutamate receptors remains to be elucidated. We used short hairpin RNA (shRNA) to knock down tomosyn in mouse primary neurons to evaluate the postsynaptic cellular function and molecular signaling regulated by tomosyn. Knockdown of tomosyn led to an increase of RhoA GTPase activity accompanied by compromised dendritic arborization, loss of dendritic spines, decreased surface expression of AMPA receptors, and reduced miniature excitatory postsynaptic current (mEPSC) frequency. Inhibiting RhoA signaling was sufficient to rescue the abnormal dendritic morphology and the surface expression of AMPA receptors. The function of tomosyn regulating RhoA is mediated through the N-terminal WD40 motif, where two variants each carrying a single nucleotide mutation in this region, were found in individuals with autism spectrum disorder (ASD). We demonstrated that these variants displayed loss-of-function phenotypes. Unlike the wild-type tomosyn, these two variants failed to restore the reduced dendritic complexity, spine density, as well as decreased surface expression of AMPA receptors in tomosyn knockdown neurons. This study uncovers a critical role of tomosyn, independent of its interaction with the SNARE machinery, in maintaining neuronal function by inhibiting RhoA activity. Further analysis of tomosyn variants also provides a potential mechanism for explaining cellular pathology in ASD.Significance StatementThis study unveils a vital role of tomosyn in the maintenance of neuronal morphology, basal synaptic transmission, and AMPA receptor surface expression that is distinct from its presynaptic role. Tomosyn affects dendritic stability and glutamate receptor trafficking via the regulation of the Rho signaling pathway and this interaction is likely independent of the interaction with the dendritic SNARE complex, such as syntaxin-4. The WD40 domain of tomosyn is necessary to conduct the Rho regulation and two autism-associated variants localized at the WD40 domain perturb this function. The current study reveals a novel molecular link between dendritic stability and synaptic function, which could advance a greater understanding of the cellular pathologies involved in neurodevelopmental disorders, such as ASD.

scholarly journals A Caenorhabditis elegans Model for Integrating the Functions of Neuropsychiatric Risk Genes Identifies Components Required for Normal Dendritic Morphology

2020 ◽  
Vol 10 (5) ◽  
pp. 1617-1628 ◽  
Author(s):  
Cristina Aguirre-Chen ◽  
Natalia Stec ◽  
Olivia Mendivil Ramos ◽  
Nuri Kim ◽  
Melissa Kramer ◽  
...  
Keyword(s):  
Cell Fate ◽  
Autism Spectrum ◽  
Dendritic Morphology ◽  
Dendritic Arborization ◽  
Neuronal Morphology ◽  
Risk Genes ◽  
C Elegans ◽  
Link Type ◽  
Neuropsychiatric Diseases ◽  
Screening Platform

Analysis of patient-derived DNA samples has identified hundreds of variants that are likely involved in neuropsychiatric diseases such as autism spectrum disorder (ASD) and schizophrenia (SCZ). While these studies couple behavioral phenotypes to individual genotypes, the number and diversity of candidate genes implicated in these disorders highlights the fact that the mechanistic underpinnings of these disorders are largely unknown. Here, we describe a RNAi-based screening platform that uses C. elegans to screen candidate neuropsychiatric risk genes (NRGs) for roles in controlling dendritic arborization. To benchmark this approach, we queried published lists of NRGs whose variants in ASD and SCZ are predicted to result in complete or partial loss of gene function. We found that a significant fraction (>16%) of these candidate NRGs are essential for dendritic development. Furthermore, these gene sets are enriched for dendritic arbor phenotypes (>14 fold) when compared to control RNAi datasets of over 500 human orthologs. The diversity of PVD structural abnormalities observed in these assays suggests that the functions of diverse NRGs (encoding transcription factors, chromatin remodelers, molecular chaperones and cytoskeleton-related proteins) converge to regulate neuronal morphology and that individual NRGs may play distinct roles in dendritic branching. We also demonstrate that the experimental value of this platform by providing additional insights into the molecular frameworks of candidate NRGs. Specifically, we show that ANK2/UNC-44 function is directly integrated with known regulators of dendritic arborization and suggest that altering the dosage of ARID1B/LET-526 expression during development affects neuronal morphology without diminishing aspects of cell fate specification.

Author response for "Tomosyn regulates the small RhoA GTPase to control the dendritic stability of neurons and the surface expression of AMPA receptors"

2020 ◽  
Author(s):  
Wenjuan Shen ◽  
Michaela B. C. Kilander ◽  
Morgan S. Bridi ◽  
Jeannine A. Frei ◽  
Robert F. Niescier ◽  
...  
Keyword(s):  
Ampa Receptors ◽  
Surface Expression ◽  
Author Response ◽  
Rhoa Gtpase

scholarly journals Valproic acid-exposed astrocytes impair inhibitory synapse formation and function

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kotomi Takeda ◽  
Takuya Watanabe ◽  
Kohei Oyabu ◽  
Shuntaro Tsukamoto ◽  
Yuki Oba ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Synaptic Transmission ◽  
Neurodevelopmental Disorders ◽  
Synapse Formation ◽  
Autism Spectrum ◽  
Vital Role ◽  
Neuronal Morphology ◽  
Inhibitory Neurons ◽  
Inhibitory Synapses ◽  
The Impact

AbstractValproic acid (VPA) is widely prescribed to treat epilepsy. Maternal VPA use is, however, clinically restricted because of the severe risk that VPA may cause neurodevelopmental disorders in offspring, such as autism spectrum disorder. Understanding the negative action of VPA may help to prevent VPA-induced neurodevelopmental disorders. Astrocytes play a vital role in neurodevelopment and synapse function; however, the impact of VPA on astrocyte involvement in neurodevelopment and synapse function has not been examined. In this study, we examined whether exposure of cultured astrocytes to VPA alters neuronal morphology and synapse function of co-cultured neurons. We show that synaptic transmission by inhibitory neurons was small because VPA-exposed astrocytes reduced the number of inhibitory synapses. However, synaptic transmission by excitatory neurons and the number of excitatory synapses were normal with VPA-exposed astrocytes. VPA-exposed astrocytes did not affect the morphology of inhibitory neurons. These data indicate that VPA-exposed astrocytes impair synaptogenesis specifically of inhibitory neurons. Our results indicate that maternal use of VPA would affect not only neurons but also astrocytes and would result in perturbed astrocyte-mediated neurodevelopment.

scholarly journals BDNF/TrkB mediates long-distance dendritic growth by activating CREB/PI3K-mTOR-dependent translation in neuronal cell bodies

2020 ◽  
Author(s):  
G Moya-Alvarado ◽  
F.C Bronfman
Keyword(s):  
Cortical Neurons ◽  
Dendritic Growth ◽  
Neuronal Cell ◽  
Protein Translation ◽  
Dendritic Arborization ◽  
Neuronal Morphology ◽  
Neuronal Cell Body ◽  
Long Distance ◽  
Bdnf Signaling

ABSTRACTBrain-Derived Neurotrophic Factor (BDNF) is broadly expressed in many circuits of the central nervous system (CNS). It binds TrkB and p75 to trigger different signaling pathways, including ERK1/2 and PI3K-mTOR, to induce dendritic growth and synaptic plasticity. When binding to BDNF, TrkB and p75 are endocytosed to signaling endosomes to continue signaling inside the cell. Whether BDNF/TrkB-p75 signaling endosomes in axons are regulating long-distance signaling in cell bodies to modify neuronal morphology is unknown. Here, we studied the functional role of BDNF signaling endosomes in long-distance regulation of dendritic growth using compartmentalized cultures of rat and mouse cortical neurons derived from p75exonIII knock-out or TrkBF616A knock-in mice. By applying BDNF to distal axons, we showed the capacity of axonal BDNF to increase dendritic arborization in cell bodies. This process depended on TrkB activity, but not p75 expression. In axons, BDNF/TrkB co-localized with Rab5 endosomes and increased active Rab5. Also, dynein was required for BDNF long-distance signaling, consistent with sorting and transport of signaling endosomes. Using neurons derived from TrkBF616A knock-in mice and the 1NM-PP1 inhibitor, we were able to demonstrate that TrkB receptors activated in the axons by BDNF, were required in the neuronal cell body to increase TrkB activity and phosphorylation of CREB. Also, we were able to visualize endosomes containing activated TrkB. PI3K activity was not required in the axons for dynein dependent BDNF responses. However, dendritic arborization induced by axonal BDNF signaling required both nuclear CREB and PI3K activation in cell bodies. Consistently, axonal BDNF increased protein translation in cell bodies and CREB and PI3K and mTOR activity were required for this process. Altogether, these results show that BDNF/TrkB signaling endosomes generated in axons allows long-distance control of dendritic growth coordinating both transcription and protein translation. Our results suggest a role of BDNF-TrkB signaling endosomes wiring circuits in the CNS.

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