Dendritic Integration Dysfunction in Neurodevelopmental Disorders

Abstract

Neurodevelopmental disorders (NDDs) that affect cognition, social interaction, and learning, including autism spectrum disorder (ASD) and intellectual disability (ID), have a strong genetic component. Our current understanding of risk genes highlights two main groups of dysfunction: those in genes that act as chromatin modifiers and those in genes that encode for proteins localized at or near synapses. Understanding how dysfunction in these genes contributes to phenotypes observed in ASD and ID remains a major question in neuroscience. In this review, we highlight emerging evidence suggesting that dysfunction in dendrites – regions of neurons that receive synaptic input – may be key to understanding features of neuronal processing affected in these disorders. Dendritic integration plays a fundamental role in sensory processing, cognition, and conscious perception, processes hypothesized to be impaired in NDDs. Many high-confidence ASD genes function within dendrites where they control synaptic integration and dendritic excitability. Further, increasing evidence demonstrates that several ASD/ID genes, including chromatin modifiers and transcription factors, regulate the expression or scaffolding of dendritic ion channels, receptors, and synaptic proteins. Therefore, we discuss how dysfunction of subsets of NDD-associated genes in dendrites leads to defects in dendritic integration and excitability and may be one core phenotype in ASD and ID.

Physical and functional convergence of the autism risk genesScn2aandAnk2in neocortical pyramidal cell dendrites

“…Haploinsufficiency of Ank2 in prefrontal neocortical neurons caused dendritic excitability and synaptic deficits, due to reduced Na V channel density within the dendritic membrane, which phenocopies Scn2a haploinsufficient conditions. These findings establish a direct, convergent mechanism between two major ASD-associated genes and add to a growing body of literature demonstrating dysfunction in dendritic excitability in ASD (Brager and Johnston, 2014; Brandalise et al, 2022; Johnston et al, 2016; Nelson and Bender, 2021).…”

“…Emerging evidence indicates that other ASD-associated genes may similarly affect neocortical pyramidal cell dendritic integration, either via regulation of Na V s (Brandalise et al, 2022), other channels that influence dendritic excitability (Bock and Stuart, 2016;Gonzalez et al, 2022;Harnett et al, 2013Harnett et al, , 2015Magee and Johnston, 1995;Shah, 2014), or changes in excitation that promote dendritic non-linear events or inhibition that limits such activity (Gidon and Segev, 2012;Megías et al, 2001;Ujfalussy et al, 2015;Wilson et al, 2012;Zhang et al, 2013). These effects can be overt, with ASD-associated variants directly affecting genes encoding dendritic or synaptic proteins in question, or covert, with ASD-associated variants instead affecting gene regulatory elements that in turn alter protein expression (reviewed in Nelson and Bender, 2021).…”

Contribution of the dihydropyrimidinase-like proteins family in synaptic physiology and in neurodevelopmental disorders

“…Consistently with the major role of DPYSL proteins in dendritic organization and in formation and maturation of synapse, various studies suggested that they would contribute in the pathophysiology of psychiatric diseases such as schizophrenia and NDDs ( Table 3 ; Edgar et al, 2000 ; Charrier et al, 2003 ; Hong et al, 2005 ; Beasley et al, 2006 ; Bader et al, 2012 ; Braunschweig et al, 2013 ; Yamashita et al, 2013 ; Lee et al, 2015 ; Quach et al, 2015 ; Tsutiya et al, 2017 ; Quach et al, 2021 ; Murtaza et al, 2022 ) (database SFARI, denovo-db). Interestingly, dendritic and spine dysfunctions are described in NDDs including schizophrenia, Down’s syndrome, Fragile X syndrome, Rett syndrome and ASD ( Huttenlocher, 1991 ; Kaufmann and Moser, 2000 ; Martínez-Cerdeño, 2017 ; Nelson and Bender, 2021 ; Quach et al, 2021 ). Dpysl KO mouse models displayed morphological abnormalities in neurons as well as behavioral defects similar to those found in schizophrenia (hyperactivity, learning and memory deficits...) or in ASD ( Yamashita et al, 2013 ; Nakamura et al, 2016 ; Tsutiya et al, 2017 ; Ohtani-Kaneko, 2019 ).…”

Corticothalamic Pathways From Layer 5: Emerging Roles in Computation and Pathology

“…In addition to these findings, it is increasingly understood that dendritic integration in pyramidal neurons, which plays essential roles in sensory processing and cognition, is disrupted in a range of neurodevelopmental disorders (Nelson and Bender, 2021). For example, autism spectrum disorder is associated with genetic changes that elicit functional, morphological, and organizational alterations in L5, but it is not understood if and how these cortical changes affect the rest of the CTC network (Nelson and Bender, 2021).…”