Investigating mechanisms underlying neurodevelopmental phenotypes of autistic and intellectual disability disorders: a perspective

Abstract

Brain function and behavior undergo significant plasticity and refinement, particularly during specific critical and sensitive periods. In autistic and intellectual disability (ID) neurodevelopmental disorders (NDDs) and their corresponding genetic mouse models, impairments in many neuronal and behavioral phenotypes are temporally regulated and in some cases, transient. However, the links between neurobiological mechanisms governing typically normal brain and behavioral development (referred to also as "neurotypical" development) and timing of NDD impairments are not fully investigated. This perspective highlights temporal patterns of synaptic and neuronal impairment, with a restricted focus on autism and ID types of NDDs. Given the varying known genetic and environmental causes for NDDs, this perspective proposes two strategies for investigation: (1) a focus on neurobiological mechanisms underlying known critical periods in the (typically) normal-developing brain; (2) investigation of spatio-temporal expression profiles of genes implicated in monogenic syndromes throughout affected brain regions. This approach may help explain why many NDDs with differing genetic causes can result in overlapping phenotypes at similar developmental stages and better predict vulnerable periods within these disorders, with implications for both therapeutic rescue and ultimately, prevention.

Keywords: critical periods; development; gene expression; neurodevelopmental disorders; phenotype.

Figure 1

Several NDD-associated genes function at the synapse. Monogenic NDD genes (red) expressed in the synapse, illustrated here postsynaptically, mediate spine morphology changes via small GTPase-mediated signaling pathways and F-actin in response to synaptic activation via BDNF and glutamatergic excitation. Abbreviations: 4EBP1, eukaryotic translation initiation factor 4E-binding protein 1; AMPA, 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid receptor; Cdc42, cell division cycle 42; CYFIP, cytoplasmic binding partner of fragile X protein; eIF4E, eukaryotic translation initiation factor 4E; FMRP, fragile X mental retardation protein; LimK1, LIM domain kinase 1; mGluR5 metabotropic glutamate receptor subunit 5; mTOR1, mammalian target of rapamycin 1; NMDA, N-Methyl-D-aspartic acid or N-Methyl-D-aspartate Receptor; OPHN1, oligophrenin-1; PAK, P21-activated kinase; Rac1, ras-related C3 botulinum toxin substrate; Rheb, Ras homolog enriched in brain; RhoA, ras homolog gene family, member A; TrkB, TrkB tyrosine kinase; Tsc 1, tuberous sclerosis protein 1; Tsc 2, tuberous sclerosis protein 2.

Figure 2

Two ways in which dysfunction of NDD genes can dysregulate critical periods. A critical period is shown here as the timeframe between “1” and “2”. (A) In this scenario, the critical period is caused by external factors (blue bar) not related to the NDD gene and expression of the NDD gene in wild-type is not necessarily atlered before, during or after the critical period (red area). However, the NDD gene plays a role downstream of these external factors and is necessary for phenotypic change to take place, thereby indirectly regulating not the occurrence but the outcome of the critical period. Hence, dysfunction of the gene leads to an impaired critical period. (B) Increased NDD gene expression (red area) directly regulates the critical period and causes it to occur, independent of external factors. Therefore, dysfunction of the NDD gene causes the critical period to be absent completely. (C) In both scenarios, the NDD gene is necessary for the phenotypic change that takes place during the critical period (“WT” vs “KO”), represented here by maturation of spine morphology.

Figure 3

Temporal regulation of genes for syndromic NDDs during pre- and postnatal brain development. Developmental profiles of RNA levels for specific monogenic ID and ASD genes in pre- and postnatal development, in telencephalon and thalamic (Area P2) regions. Data extracted from Allen Developing Mouse Brain Atlas Website: ©2012 Allen Institute for Brain Science. Allen Developing Mouse Brain Atlas [Internet]. Abbreviations: Fmr1, Fragile X mental retardation 1; LimK1, LIM domain kinase 1; NF1, neurofibromin; SHANK3, SH3 and multiple ankyrin repeat domains 3; TSC1/TSC2, tuberous sclerosis protein 1/2; UBE3A, ubiquitin-protein ligase E3A.