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

Kroon T, Sierksma MC, Meredith RM - Front Syst Neurosci (2013)

Bottom Line: Brain function and behavior undergo significant plasticity and refinement, particularly during specific critical and sensitive periods.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Integrative Neurophysiology, Centre for Neurogenomics and Cognitive Research (CNCR), Neuroscience Campus Amsterdam, VU University Amsterdam, Netherlands.

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.

No MeSH data available.


Related in: MedlinePlus

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].3 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.
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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].3 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.

Mentions: The developmental regulation of spatial patterns of individual gene expression in the neurotypical brain includes many known NDD candidate genes for monogenic syndromes (Allen Brain Developing Human and Mouse Brain Atlas,2). Of interest, many genes linked to ASD show dynamic changes in expression in subplate layers of the mouse cortex, suggesting disruption of early developmentally regulated NDD candidates (Hoerder-Suabedissen et al., 2013). However, the direct functional effects of these gene changes are not yet known. Prominent genes underlying ID and ASD, including Fmr1, neurofibromin (NF1) and TSC 1/ 2 show strong developmental mRNA upregulation particularly from late embryonic stages onwards (Figure 3). For Fmr1, this upregulation is transient, peaking between postnatal days (P) 4 and 14 in telencephalic and thalamic defined regions before decreasing by P28 (Figure 3). Given that transient phenotypes in thalamocortical and cortico-cortical synaptic pathways occur in the Fmr1-KO mouse model, it is plausible that these temporal impairments only arise during periods of peak expression for the Fmr1 gene. That is to say, irregularities in an NDD only result in a phenotype at the time when the NDD gene peak expression would usually occur in neurotypical development. No synaptic NDD phenotype is observed if the gene is not prominently being expressed in that brain region and as such, there is no noticeable impairment in the KO mouse model at that stage.


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

Kroon T, Sierksma MC, Meredith RM - Front Syst Neurosci (2013)

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].3 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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814085&req=5

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].3 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.
Mentions: The developmental regulation of spatial patterns of individual gene expression in the neurotypical brain includes many known NDD candidate genes for monogenic syndromes (Allen Brain Developing Human and Mouse Brain Atlas,2). Of interest, many genes linked to ASD show dynamic changes in expression in subplate layers of the mouse cortex, suggesting disruption of early developmentally regulated NDD candidates (Hoerder-Suabedissen et al., 2013). However, the direct functional effects of these gene changes are not yet known. Prominent genes underlying ID and ASD, including Fmr1, neurofibromin (NF1) and TSC 1/ 2 show strong developmental mRNA upregulation particularly from late embryonic stages onwards (Figure 3). For Fmr1, this upregulation is transient, peaking between postnatal days (P) 4 and 14 in telencephalic and thalamic defined regions before decreasing by P28 (Figure 3). Given that transient phenotypes in thalamocortical and cortico-cortical synaptic pathways occur in the Fmr1-KO mouse model, it is plausible that these temporal impairments only arise during periods of peak expression for the Fmr1 gene. That is to say, irregularities in an NDD only result in a phenotype at the time when the NDD gene peak expression would usually occur in neurotypical development. No synaptic NDD phenotype is observed if the gene is not prominently being expressed in that brain region and as such, there is no noticeable impairment in the KO mouse model at that stage.

Bottom Line: Brain function and behavior undergo significant plasticity and refinement, particularly during specific critical and sensitive periods.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Integrative Neurophysiology, Centre for Neurogenomics and Cognitive Research (CNCR), Neuroscience Campus Amsterdam, VU University Amsterdam, Netherlands.

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.

No MeSH data available.


Related in: MedlinePlus