Dendritic spine and synapse pathology in chromatin modifier-associated autism spectrum disorders and intellectual disability

Abstract

Formation of dendritic spine and synapse is an essential final step of brain wiring to establish functional communication in the developing brain. Recent findings have displayed altered dendritic spine and synapse morphogenesis, plasticity, and related molecular mechanisms in animal models and post-mortem human brains of autism spectrum disorders (ASD) and intellectual disability (ID). Many genes and proteins are shown to be associated with spines and synapse development, and therefore neurodevelopmental disorders. In this review, however, particular attention will be given to chromatin modifiers such as AT-Rich Interactive Domain 1B (ARID1B), KAT8 regulatory non-specific lethal (NSL) complex subunit 1 (KANSL1), and WD Repeat Domain 5 (WDR5) which are among strong susceptibility factors for ASD and ID. Emerging evidence highlights the critical status of these chromatin remodeling molecules in dendritic spine morphogenesis and synaptic functions. Molecular and cellular insights of ARID1B, KANSL1, and WDR5 will integrate into our current knowledge in understanding and interpreting the pathogenesis of ASD and ID. Modulation of their activities or levels may be an option for potential therapeutic treatment strategies for these neurodevelopmental conditions.

The overlapping genetic architecture of psychiatric disorders and cortical brain structure

“…Genes jointly associated with brain structures and ASD showed the strongest enrichment in “methylated histone binding” (p=0.001). rs147317628, which is jointly associated with ASD and 62% of brain measures, is an intronic variant in KANSL1 , a crucial chromatin modifier implicated in the pathogenesis of ASD 62 . The top-ranked gene set involving genes jointly associated with brain structure and BD is “cytoplasmic sequestering of protein” (p=2.46×10 −5 ), which is important for the maintenance of protein transport and protein location within mammalian cells.…”

Autism Spectrum Disorder: Brain Areas Involved, Neurobiological Mechanisms, Diagnoses and Therapies

“…Autism Spectrum Disorder, ASD, is a neurodevelopmental brain complex disease established in growing fetuses and very young children during early development. ASD is caused by the altered expression of specific genes [1,2]. Its identification was not an early discovery.…”

“…ASD appears as the most significant disease in the field. Initially, its definition was widely debated; now, it is generally accepted as the complex neurodevelopmental disorder established during, and caused by, genetic and environmental perturbations [1,2].…”

“…In addition to their altered neurogenic effects, ASD was co-affected by abnormalities. Some properties of the latter, however, are still largely uncharacterized [1,2]. The principal targets of the disease are the synapses, in particular the post-synapses of dendrites, both flat and spiny (Figure 1).…”

“…These other subcategories are not presented in parallel to ASD but rather only mentioned. General definitions such as intellectual disability (ID) and a few others, employed in previous publications for the completion of ASD properties [2], are not presented here in detail. In other words, our intention has been to inform our readers about ASD, including knowledge established recently.…”