scholarly journals The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction

2020 ◽  
Author(s):  
Helen M. Belalcazar ◽  
Emily L. Hendricks ◽  
Sumaira Zamurrad ◽  
Faith L.W. Liebl ◽  
Julie Secombe
Keyword(s):  
Neuromuscular Junction ◽  
Histone Demethylase ◽  
Synaptic Function ◽  
Complex Nature ◽  
Synaptic Structure ◽  
Genes Encoding ◽  
Demethylase Activity ◽  
Larval Neuromuscular Junction ◽  
And Function ◽  
Structure And Activity

SummaryMutations in the genes encoding the KDM5 family of histone demethylases are observed in individuals with intellectual disability (ID). Despite clear evidence linking KDM5 function to neurodevelopmental pathways, how this family of proteins impacts transcriptional programs to mediate synaptic structure and activity remains unclear. Using the Drosophila larval neuromuscular junction (NMJ), we show that KDM5 is required for neuroanatomical development and synaptic function. The JmjC-domain encoded histone demethylase activity of KDM5, which is expected to be diminished by many ID-associated alleles and required for appropriate synaptic morphology and neurotransmission. The C5HC2 zinc finger of KDM5 is also involved, as an ID-associated mutation in this motif reduces NMJ bouton number but increases bouton size. KDM5 therefore uses demethylase-dependent and independent mechanisms to regulate NMJ structure and activity, highlighting the complex nature by which this chromatin modifier carries out its neuronal gene regulatory programs.

scholarly journals Neurexin–Neuroligin 1 regulates synaptic morphology and functions via the WAVE regulatory complex in Drosophila neuromuscular junction

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Guanglin Xing ◽  
Moyi Li ◽  
Yichen Sun ◽  
Menglong Rui ◽  
Yan Zhuang ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Molecular Mechanisms ◽  
Postsynaptic Membrane ◽  
Synaptic Function ◽  
Actin Assembly ◽  
Actin Reorganization ◽  
Synaptic Structure ◽  
Structural And Functional Properties ◽  
Regulatory Complex ◽  
And Function

Neuroligins are postsynaptic adhesion molecules that are essential for postsynaptic specialization and synaptic function. But the underlying molecular mechanisms of neuroligin functions remain unclear. We found that Drosophila Neuroligin 1 (DNlg1) regulates synaptic structure and function through WAVE regulatory complex (WRC)-mediated postsynaptic actin reorganization. The disruption of DNlg1, DNlg2, or their presynaptic partner neurexin (DNrx) led to a dramatic decrease in the amount of F-actin. Further study showed that DNlg1, but not DNlg2 or DNlg3, directly interacts with the WRC via its C-terminal interacting receptor sequence. That interaction is required to recruit WRC to the postsynaptic membrane to promote F-actin assembly. Furthermore, the interaction between DNlg1 and the WRC is essential for DNlg1 to rescue the morphological and electrophysiological defects in dnlg1 mutants. Our results reveal a novel mechanism by which the DNrx-DNlg1 trans-synaptic interaction coordinates structural and functional properties at the neuromuscular junction.

scholarly journals The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction

Cell Reports ◽  
2021 ◽  
Vol 34 (7) ◽  
pp. 108753 ◽  
Author(s):  
Helen M. Belalcazar ◽  
Emily L. Hendricks ◽  
Sumaira Zamurrad ◽  
Faith L.W. Liebl ◽  
Julie Secombe
Keyword(s):  
Neuromuscular Junction ◽  
Structure And Function ◽  
Histone Demethylase ◽  
Synaptic Structure ◽  
And Function

scholarly journals Effect of salbutamol on neuromuscular junction function and structure in a mouse model of DOK7 congenital myasthenia

2020 ◽  
Vol 29 (14) ◽  
pp. 2325-2336 ◽  
Author(s):  
Richard G Webster ◽  
An E Vanhaesebrouck ◽  
Susan E Maxwell ◽  
Judith A Cossins ◽  
Weiwei Liu ◽  
...  
Keyword(s):  
Weight Gain ◽  
Neuromuscular Junction ◽  
Mouse Model ◽  
Structural Integrity ◽  
Ex Vivo ◽  
Adrenergic Agonists ◽  
Mice Model ◽  
Synaptic Structure ◽  
Perinatal Lethality ◽  
And Function

Abstract Congenital myasthenic syndromes (CMS) are characterized by fatigable muscle weakness resulting from impaired neuromuscular transmission. β2-adrenergic agonists are an effective treatment for DOK7-CMS. DOK7 is a component within the AGRN-LRP4-MUSK-DOK7 signalling pathway that is key for the formation and maintenance of the synaptic structure of the neuromuscular junction (NMJ). The precise mechanism of action of β2-adrenergic agonists at the NMJ is not fully understood. In this study, we investigated whether β2-adrenergic agonists improve both neurotransmission and structural integrity of the NMJ in a mouse model of DOK7-CMS. Ex-vivo electrophysiological techniques and microscopy of the NMJ were used to study the effect of salbutamol, a β2-adrenergic agonist, on synaptic structure and function. DOK7-CMS model mice displayed a severe phenotype with reduced weight gain and perinatal lethality. Salbutamol treatment improved weight gain and survival in DOK7 myasthenic mice. Model animals had fewer active NMJs, detectable by endplate recordings, compared with age-matched wild-type littermates. Salbutamol treatment increased the number of detectable NMJs during endplate recording. Correspondingly, model mice had fewer acetylcholine receptor-stained NMJs detected by fluorescent labelling, but following salbutamol treatment an increased number were detectable. The data demonstrate that salbutamol can prolong survival and increase NMJ number in a severe model of DOK7-CMS.

Synaptopathy: dysfunction of synaptic function?

2010 ◽  
Vol 38 (2) ◽  
pp. 443-444 ◽  
Author(s):  
Nils Brose ◽  
Vincent O'Connor ◽  
Paul Skehel
Keyword(s):  
Animal Experimentation ◽  
Structure And Function ◽  
Synaptic Function ◽  
Cellular Systems ◽  
Brain Diseases ◽  
Psychiatric Disease ◽  
Synaptic Dysfunction ◽  
A Value ◽  
Synaptic Structure ◽  
And Function

Synaptopathy is an increasingly popular term used to define key features of neurodegenerative and psychiatric disease. It implies that disruptions in synaptic structure and function are potentially the major determinant of such brain diseases. The Synaptopathies: Dysfunction of Synaptic Function Biochemical Society Focused Meeting brought together several invited speakers, supplemented with short communications from young scientists, who addressed this possibility. The talks spanned the full gamut of approaches that brought molecular, cellular, systems and whole-animal experimentation together to address how fundamental synaptic biology was increasingly informing on dysfunction in disease. The disease and models thereof discussed included Alzheimer's disease, prions, Huntington's disease, Parkinson's disease, schizophrenia and autism. The audience were asked to reflect on whether synaptopathy, although attractive and conceptually useful, provided a significant explanation as the cause of these major diseases. The breadth of the meeting reinforced the complexity of these brain diseases, supported the significance of synaptic dysfunction in disease, but left open the issue as to whether the prime cause of these disorders could be resolved as simple synaptic dysfunction. Thus, despite revealing a value of synaptopathy, further investigation will be required to reveal its balance in the cause and effect in each of the major brain diseases.

scholarly journals Plum is a novel regulator of synaptic function and muscle size in D. melanogaster

2018 ◽  
Author(s):  
Hrvoje Augustin ◽  
Jereme G. Spiers ◽  
Nathaniel S. Woodling ◽  
Joern R. Steinert ◽  
Linda Partridge
Keyword(s):  
Body Weight ◽  
Neuromuscular Junction ◽  
Synaptic Function ◽  
Negative Regulator ◽  
Therapeutic Interventions ◽  
Muscle Size ◽  
Model Organisms ◽  
Neuromuscular System ◽  
Age Related ◽  
And Function

ABSTRACTAlterations in the neuromuscular system underlie several neuromuscular diseases and play critical roles in the development of sarcopenia, the age-related loss of muscle mass and function. Mammalian Myostatin (MST) and GDF11, members of the TGF-β superfamily of growth factors, are powerful regulators of muscle size in both model organisms and humans. Myoglianin (MYO), the Drosophila homolog of MST and GDF11, is a strong inhibitor of synaptic function and structure at the neuromuscular junction (NMJ), and a negative regulator of body weight and muscle size and function in flies. Here, we identified Plum, a cell surface immunoglobulin homologous to mammalian developmental regulators Protogenin and Nope, as a modulator of MYO function in the larval neuromuscular system. Reduction of Plum specifically in the larval body-wall muscles abolishes the previously demonstrated positive effect of attenuated MYO signalling on both muscle size and neuromuscular junction structure and function, likely by de-sequestrating the remaining MYO. In addition, downregulation of Plum on its own results in decreased synaptic strength and body weight, classifying Plum as a (novel) regulator of neuromuscular function and body (muscle) size. These findings offer new insights into possible regulatory mechanisms behind ageing- and disease-related neuromuscular dysfunctions in humans and identify potential targets for therapeutic interventions.

scholarly journals Glial Cells Maintain Synaptic Structure and Function and Promote Development of the Neuromuscular Junction In Vivo

Neuron ◽  
2003 ◽  
Vol 40 (3) ◽  
pp. 563-580 ◽  
Author(s):  
Linga V. Reddy ◽  
Samir Koirala ◽  
Yoshie Sugiura ◽  
Albert A. Herrera ◽  
Chien-Ping Ko
Keyword(s):  
Neuromuscular Junction ◽  
Glial Cells ◽  
Structure And Function ◽  
Synaptic Structure ◽  
And Function

scholarly journals Astroglial dysfunctions drive aberrant synaptogenesis in developing brain with lengthy general anesthesia

2018 ◽  
Author(s):  
Bin Zhou ◽  
Lingmin Chen ◽  
Ping Liao ◽  
Lu Huang ◽  
Zhuo Chen ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Synaptic Function ◽  
Developing Brain ◽  
Actin Binding ◽  
General Anesthetics ◽  
Cellular Mechanisms ◽  
Genetic Intervention ◽  
Synaptic Structure ◽  
And Function

AbstractLengthy use of general anesthetics (GAs) causes cognitive deficits in developing brain, which has raised significant clinical concerns such that FDA is warning on the use of GAs in children younger than 3 years. However, the molecular and cellular mechanisms for GAs-induced neurotoxicity remain largely unknown. Here we report that sevoflurane, a commonly used GA in pediatrics, causes compromised astrocyte morphogenesis, spatiotemporally correlated to the synaptic overgrowth with reduced synaptic function in developing cortex in a regional-, exposure-length- and age-specific manner. Sevoflurane disrupts astrocyte Ca2+ homeostasis both acutely and chronically, which leads to the down regulation of Ezrin, an actin-binding membrane protein, which we found is critically involved in astrocyte morphogenesis in vivo. Importantly, in normal developing brain, the genetic intervention of astrocyte morphogenesis is sufficient to produce the aberrant synaptic structure and function virtually identical to the ones induced by lengthy sevoflurane exposure. Our data uncover that astrocytes are unexpectedly central targets for GAs to exert toxic effects, and that astrocyte morphological integrity is crucial for synaptogenesis in the developing brain.

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