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

Tim Kroon,Martijn C Sierksma,Rhiannon M Meredith

doi:10.3389/fnsys.2013.00075

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.

Highlights

Disruption or loss of an early critical period can influence both functional and structural connectivity in the affected region but in other areas of the sensory processing system and result in altered sensory perception. Applying this principle to neurodevelopmental disorders (NDDs), early or transient alterations in synaptic phenotypes during known critical periods could account for later aberrations in synaptic function, morphology and potentially even behavioral impairments of sensory information processing that characterize many of these disorders
Given the tightly regulated growth of the brain and sequential patterns of development from one synaptic network to another (Ben-Ari and Spitzer, 2010), we propose that long-range connectivity may be vulnerable in NDDs, especially where the NDD-linked genes are strongly expressed at prenatal or early postnatal time-windows in brain development (Meredith et al, 2012)
TESTABLE HYPOTHESES FOR VALIDATION IN NDDs On these bases outlined, we propose three testable hypotheses (Box 1) to guide further investigation into neurobiological mechanisms for pathology of NDDs: During development of sensory systems in the neurotypical brain, critical periods occur in a sequential pattern from brainstem, to thalamus to cortical regions as synapses form, refine and mature

Summary

Introduction

No differences in synaptic networks or critical periods in NDDs occur prior to the neurotypical pre- or postnatal expression of the NDD gene in that brain region. Transient phenotypes are observed in thalamocortical pathways: in Fmr1-KO mice, enhanced NMDA/AMPA synaptic ratios and altered plasticity occur during the first but not by the end of the second postnatal week, indicating developmental delays within the neurotypical critical period for this pathway (Harlow et al, 2010).

Results

Conclusion