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.

Keywords: ARID1B; KANSL1; WDR5; autism; dendritic spine; intellectual disability; synapse.

FIGURE 1

Chromatin remodeling by the BRG1/BRM-associated factor (BAF) complex. (A) AT-Rich Interactive Domain 1B (ARID1B) acts as a scaffolding protein that holds together the BAF complex, giving it the ability to interact with chromatin. Without ARID1B, the complex is destabilized and therefore unlikely to remodel chromatin correctly. The BAF complex regulates nuclear gene transcription by remodeling a chromatin structure that contains its target genes. The complex performs histone modifications including acetylation of histone H3 at lysine 9 (H3K9ac). Thereby, chromatin detangles and exposes naked gene areas to the transcription initiation machinery (TIM). Multiple enzymes are collectively involved in the histone modification at the regulatory regions of their target genes. Although histone H3 trimethylation at lysine 4 (H3K4me3) is also impacted by the BAF complex as well as histone H3 trimethylation at lysine 27 (H3K27me3), they are not featured in this specific example. (B) Normal neurons express spine and synaptic proteins that move to synaptic compartments and direct synaptic maturation. However, Arid1b haploinsufficient neurons lack proper expression of synapse-associated genes, leading to underdeveloped dendritic spines.

FIGURE 2

Gene expression regulation by the non-specific lethal (NSL) complex at chromatin. The NSL complex regulates nuclear gene transcription by modifying histone H4 at lysine 16 (H4K16) and histone H3 at lysine 4 (H3K4). The complex contains multiple histone modifying enzymes and co-factors, including histone methyltransferase (HMT) and KAT8. Thus, the access of transcription factors is regulated for appropriate gene expression. These histone modifications are supported by KAT8 regulatory non-specific lethal (NSL) complex subunit 1 (KANSL1) and/or WD Repeat Domain 5 (WDR5).