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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

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.
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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.

Mentions: First, the underlying pathology of NDDs could arise through aberrant interactions during existing critical period mechanisms that are in place during neurotypical development (Figures 2A, C). For example, both ocular dominance plasticity and mapping of frequency representation during their respective critical periods are impaired in the Fmr1 KO mouse but can be restored by reduction of metabotropic glutamate receptor subunit 5 (mGluR5) expression or pharmacological blockade (Dolen et al., 2007; Kim et al., 2013). The Fmr1 gene product, FMRP, is activated following mGluR5 stimulation and regulates synaptic mRNA translation and (Weiler et al., 1997) mGluR5 activation is necessary for certain types of synaptic plasticity (Huber et al., 2000; Raymond et al., 2000). Attenuation of mGluR5 signaling dysregulates both experience-dependent NMDA receptor expression and synaptic plasticity in young and adult visual cortex, respectively (Tsanov and Manahan-Vaughan, 2009). Therefore, the absence of FMRP in FXS affects the level of synaptic plasticity via mGluR5-mediated signaling dysregulation, which in turn affects the level of response during the critical period for ocular dominance.


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

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

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

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

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.
Mentions: First, the underlying pathology of NDDs could arise through aberrant interactions during existing critical period mechanisms that are in place during neurotypical development (Figures 2A, C). For example, both ocular dominance plasticity and mapping of frequency representation during their respective critical periods are impaired in the Fmr1 KO mouse but can be restored by reduction of metabotropic glutamate receptor subunit 5 (mGluR5) expression or pharmacological blockade (Dolen et al., 2007; Kim et al., 2013). The Fmr1 gene product, FMRP, is activated following mGluR5 stimulation and regulates synaptic mRNA translation and (Weiler et al., 1997) mGluR5 activation is necessary for certain types of synaptic plasticity (Huber et al., 2000; Raymond et al., 2000). Attenuation of mGluR5 signaling dysregulates both experience-dependent NMDA receptor expression and synaptic plasticity in young and adult visual cortex, respectively (Tsanov and Manahan-Vaughan, 2009). Therefore, the absence of FMRP in FXS affects the level of synaptic plasticity via mGluR5-mediated signaling dysregulation, which in turn affects the level of response during the critical period for ocular dominance.

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