Synaptic Dysfunction in Neurodevelopmental Disorders Associated with Autism and Intellectual Disabilities
Huda Y. Zoghbi,Mark F. Bear +1 more
TLDR
Top-down approaches using human phenotypes and genetics and bottom-up approaches applying molecular, biochemical, and neurophysiological studies to genetic models of these disorders revealed unsuspected pathogenic mechanisms and identified potential therapeutic targets.Abstract:
The discovery of the genetic causes of syndromic autism spectrum disorders and intellectual disabilities has greatly informed our understanding of the molecular pathways critical for normal synaptic function. The top-down approaches using human phenotypes and genetics helped identify causative genes and uncovered the broad spectrum of neuropsychiatric features that can result from various mutations in the same gene. Importantly, the human studies unveiled the exquisite sensitivity of cognitive function to precise levels of many diverse proteins. Bottom-up approaches applying molecular, biochemical, and neurophysiological studies to genetic models of these disorders revealed unsuspected pathogenic mechanisms and identified potential therapeutic targets. Moreover, studies in model organisms showed that symptoms of these devastating disorders can be reversed, which brings hope that affected individuals might benefit from interventions even after symptoms set in. Scientists predict that insights gained from studying these rare syndromic disorders will have an impact on the more common nonsyndromic autism and mild cognitive deficits.read more
Citations
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Journal ArticleDOI
FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders
Jessica Mariani,Gianfilippo Coppola,Ping Zhang,Alexej Abyzov,Lauren E. Provini,Livia Tomasini,Mariangela Amenduni,Anna Szekely,Dean Palejev,Michael Wilson,Mark Gerstein,Elena L. Grigorenko,Katarzyna Chawarska,Kevin A. Pelphrey,James R. Howe,Flora M. Vaccarino +15 more
TL;DR: Three-dimensional neural cultures derived from induced pluripotent stem cells are used to investigate neurodevelopmental alterations in individuals with severe idiopathic ASD and show that overexpression of the transcription factor FOXG1 is responsible for the overproduction of GABAergic neurons.
Journal ArticleDOI
Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits
Guomei Tang,Kathryn Gudsnuk,Sheng-Han Kuo,Marisa L. Cotrina,Marisa L. Cotrina,Gorazd Rosoklija,Alexander A. Sosunov,Mark S. Sonders,Ellen Kanter,Candace Castagna,Ai Yamamoto,Zhenyu Yue,Ottavio Arancio,Bradley S. Peterson,Frances A. Champagne,Andrew J. Dwork,James E. Goldman,David Sulzer +17 more
TL;DR: This work reports increased dendritic spine density with reduced developmental spine pruning in layer V pyramidal neurons in postmortem ASD temporal lobe and suggests that mTOR-regulated autophagy is required for developmental spinePruning, and activation of neuronal Autophagy corrects synaptic pathology and social behavior deficits in ASD models with hyperactivated mTOR.
Journal ArticleDOI
Activity-dependent neuronal signalling and autism spectrum disorder
TL;DR: Evidence indicates that many of the genes that are mutated in autism spectrum disorder are crucial components of the activity-dependent signalling networks that regulate synapse development and plasticity.
Journal ArticleDOI
The Postsynaptic Organization of Synapses
Morgan Sheng,Eunjoon Kim +1 more
TL;DR: The postsynaptic density of excitatory synapses is especially complex and dynamic in composition and regulation; it contains hundreds of different proteins, many of which are required for cognitive function and implicated in psychiatric illness.
Journal ArticleDOI
From neural development to cognition: unexpected roles for chromatin
TL;DR: Interestingly, mutations in EZH2 and certain BAF complex components have roles in both neurodevelopmental disorders and cancer, and overlapping point mutations are suggesting functionally important residues and domains.
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