FMRP regulates mRNAs encoding distinct functions in the cell body and dendrites of CA1 pyramidal neurons DOI Creative Commons
Caryn Hale, Kirsty Sawicka,

Kevin Mora

et al.

eLife, Journal Year: 2021, Volume and Issue: 10

Published: Dec. 23, 2021

Neurons rely on translation of synaptic mRNAs in order to generate activity-dependent changes plasticity. Here, we develop a strategy combining compartment-specific crosslinking immunoprecipitation (CLIP) and translating ribosome affinity purification (TRAP) conditionally tagged mice precisely define the ribosome-bound dendritic transcriptome CA1 pyramidal neurons. We identify transcripts with differentially localized mRNA isoforms generated by alternative polyadenylation splicing, including many that have altered protein-coding capacity. Among mRNAs, FMRP targets were found be overrepresented. Cell-type-specific FMRP-CLIP TRAP microdissected neuropil revealed 383 suggests regulates functionally distinct modules dendrites cell bodies. ~15-20% encoding functions 10% chromatin modulators, dendrite body, respectively. In absence FMRP, had increased association, consistent function for translational repression. Conversely, downregulation involved regulation bodies role stabilizing containing stalled ribosomes this compartment. Together, data support model which expression nuclear proteins within different compartments single neuronal type.

Language: Английский

mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity DOI Creative Commons
Marco Pagani, Noemi Barsotti, Alice Bertero

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Oct. 19, 2021

Abstract Postmortem studies have revealed increased density of excitatory synapses in the brains individuals with autism spectrum disorder (ASD), a putative link to aberrant mTOR-dependent synaptic pruning. ASD is also characterized by atypical macroscale functional connectivity as measured resting-state fMRI (rsfMRI). These observations raise question whether excess causes ASD. Using rsfMRI, electrophysiology and silico modelling Tsc2 haploinsufficient mice, we show that spine associated -like stereotypies cortico-striatal hyperconnectivity. deficits are completely rescued pharmacological inhibition mTOR. Notably, further demonstrate children idiopathic exhibit analogous cortical-striatal hyperconnectivity, document this fingerprint enriched for ASD-dysregulated genes interacting mTOR or Tsc2. Finally, identified transcriptomic signature predominantly expressed subset autism, thereby defining segregable subtype. Our findings causally mTOR-related pathology large-scale network aberrations, revealing unifying multi-scale framework mechanistically reconciles developmental synaptopathy hyperconnectivity autism.

Language: Английский

Citations

113
GABAergic System Dysfunction in Autism Spectrum Disorders DOI Creative Commons
Haisheng Zhao,

Xijing Mao,

Cuilin Zhu

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 9

Published: Feb. 7, 2022

Autism spectrum disorder (ASD) refers to a series of neurodevelopmental diseases characterized by two hallmark symptoms, social communication deficits and repetitive behaviors. Gamma-aminobutyric acid (GABA) is one the most important inhibitory neurotransmitters in central nervous system (CNS). GABAergic neurotransmission critical for regulation brain rhythm spontaneous neuronal activities during neurodevelopment. Genetic evidence has identified some variations genes associated with GABA system, indicating an abnormal excitatory/inhibitory (E/I) ratio implicated pathogenesis ASD. However, specific molecular mechanism which synaptic transmission affect ASD remains unclear. Transgenic technology enables translating genetic into rodent models further investigate structural functional dysregulation related In this review, we summarized from human neuroimaging, postmortem, pharmacological studies, put emphasis on consequent E/I imbalance. We attempt illuminate pathophysiological role provide insights future investigation.

Language: Английский

Citations

83
Sleep and circadian disturbances in children with neurodevelopmental disorders DOI
Oliviero Bruni, Maria Breda,

Valeria Mammarella

et al.

Nature Reviews Neurology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Language: Английский

Citations

3
The Trail of axonal protein Synthesis: Origins and current functional Landscapes DOI
Joaquín Garat, Andrés Di Paolo, Guillermo Eastman

et al.

Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

2
Dendritic Spines Shape Analysis—Classification or Clusterization? Perspective DOI Creative Commons
Ekaterina Pchitskaya, Ilya Bezprozvanny

Frontiers in Synaptic Neuroscience, Journal Year: 2020, Volume and Issue: 12

Published: Sept. 30, 2020

Dendritic spines are small protrusions from dendrite membrane, where the contact with neighboring axons is formed in order to receive synaptic input. Changes size, shape and density of associated learning memory, also observed after exposure drugs abuse, a variety neurodegenerative, neurodevelopmental psychiatric disorders. Due its preeminent importance, major effort spend on developing techniques which enable visualization analysis dendritic cultured neurons, fixed slices intact brain tissue. Classification into predefined morphological groups standard approach that used neuroscience research, divided categories such as thin, mushroom stubby subclasses. In this perspective we reason accumulated evidence supports existence spine shapes continuum rather than clearly separated classes. We further suggest new approaches software tools reflecting complex their highly dynamic nature required perform valuable morphology. discuss compare recently developed algorithms rely clusterization classification, therefore level analysis. improved methods may help investigate link between function, facilitate studies memory well

Language: Английский

Citations

125
Synaptic GluN2A-Containing NMDA Receptors: From Physiology to Pathological Synaptic Plasticity DOI

Luca Franchini,

Nicolò Carrano, Mónica Di Luca

et al.

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(4), P. 1538 - 1538

Published: Feb. 24, 2020

N-Methyl-d-Aspartate Receptors (NMDARs) are ionotropic glutamate-gated receptors. NMDARs tetramers composed by several homologous subunits of GluN1-, GluN2-, or GluN3-type, leading to the existence in central nervous system a high variety receptor subtypes with different pharmacological and signaling properties. NMDAR subunit composition is strictly regulated during development activity-dependent synaptic plasticity. Given differences between GluN2 regulatory functions, here we will focus on pool containing GluN2A subunit, addressing its role both physiology pathological plasticity as well contribution these events types GluN2A-interacting proteins.

Language: Английский

Citations

98
Autism-Misregulated eIF4G Microexons Control Synaptic Translation and Higher Order Cognitive Functions DOI Creative Commons
Thomas Gonatopoulos-Pournatzis,

Rieko Niibori,

Eric W. Salter

et al.

Molecular Cell, Journal Year: 2020, Volume and Issue: 77(6), P. 1176 - 1192.e16

Published: Jan. 29, 2020

Language: Английский

Citations

96
The autism- and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour DOI Creative Commons
Nuria Domıńguez-Iturza, Adrian C. Lo, Disha Shah

et al.

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Aug. 1, 2019

Copy-number variants of the CYFIP1 gene in humans have been linked to autism spectrum disorders (ASD) and schizophrenia (SCZ), two neuropsychiatric characterized by defects brain connectivity. Here, we show that plays an important role functional connectivity callosal functions. We find Cyfip1-heterozygous mice reduced white matter architecture, similar phenotypes found patients with ASD, SCZ other disorders. Cyfip1-deficient also present decreased myelination axons, altered presynaptic function, impaired bilateral Finally, Cyfip1 deficiency leads abnormalities motor coordination, sensorimotor gating sensory perception, which are known disorder-related symptoms. These results haploinsufficiency compromises might explain its genetic association

Language: Английский

Citations

83
Autism Spectrum Disorders: Etiology and Pathology DOI Creative Commons
Ann Katrin Sauer, Janelle E. Stanton, Sakshi Hans

et al.

Exon Publications eBooks, Journal Year: 2021, Volume and Issue: unknown, P. 1 - 16

Published: Aug. 23, 2021

Autism spectrum disorders (ASD) are a group of neurodevelopmental diseases. The cause ASD is unknown, but several genetic and non-genetic risk factors have been characterized that, alone or in combination, implicated the development ASD. Currently, no diagnostic biomarkers available, diagnosis based on typical features that include repetitive behaviors, impaired social communication interaction. Several pathomechanisms such as alterations brain function, synaptic defects proposed to contribute these behaviors. In addition, processes outside central nervous system may to, modify, clinical phenotype severity. This chapter summarizes ASD, highlights important for introduces current knowledge around pathological within brain.

Language: Английский

Citations

83
Ythdf is a N6‐methyladenosine reader that modulates Fmr1 target mRNA selection and restricts axonal growth in Drosophila DOI Creative Commons

Lina Worpenberg,

Chiara Paolantoni,

Sara Longhi

et al.

The EMBO Journal, Journal Year: 2021, Volume and Issue: 40(4)

Published: Jan. 11, 2021

Abstract N6‐methyladenosine (m 6 A) regulates a variety of physiological processes through modulation RNA metabolism. This modification is particularly enriched in the nervous system several species, and its dysregulation has been associated with neurodevelopmental defects neural dysfunctions. In Drosophila , loss m A alters fly behavior, albeit underlying molecular mechanism role during development have remained elusive. Here we find that impairment pathway leads to axonal overgrowth misguidance at larval neuromuscular junctions as well adult mushroom bodies. We identify Ythdf main reader system, being required limit growth. Mechanistically, show directly interacts Fmr1, homolog Fragile X mental retardation binding protein (FMRP), inhibit translation key transcripts involved growth regulation. Altogether, this study demonstrates controls modulates Fmr1 target transcript selection.

Language: Английский

Citations

74