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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

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.
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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.

Mentions: Initial stages of synapse formation and neuronal connectivity require modulation of the cytoskeletal F-actin via the Ras homologue subfamily of Rho GTPases. Many genes underlying monogenic NDDs interact directly with Rho signaling protein pathways. (Figure 1; Ramakers, 2002; Ethell and Pasquale, 2005). This family of small-GTPases includes ras homolog gene family, member A (RhoA), ras-related C3 botulinum toxin substrate (Rac1) and cell division cycle 42 (Cdc42), which dynamically regulate protrusion and retraction of spines via cytoskeletal actin remodelling (Tashiro et al., 2000; Ethell and Pasquale, 2005). Small guanosine-5'-triphosphate hydrolyzing enzymes (GTPases) typically cycle between active GTP-bound and inactive guanosine diphosphate- (GDP) bound states. These transitions are dynamically regulated by GTPase activating proteins (GAPs), guanine nucleotide exchange factors (GEFs), and by GDP dissociation inhibitors (GDI) inhibiting the conversion to the active GTP-bound state (Sasaki and Takai, 1998). In syndromic OPHN1 ID, changes in spine morphology are caused by the absence of OPHN1, a RhoA-GAP (Govek et al., 2004). The ID Williams syndrome is linked to the LIM domain kinase 1 (LIMK1) gene, whose product mediates changes in actin and spine morphology via Cdc42 and Rac1 pathways (Edwards et al., 1999). Additionally, LIMK1 interacts with P21-activated kinases (PAKs) which also harbor mutations in many nonsyndromic human ID cases (Allen and Walsh, 1999). Rho family members are activated by extracellular stimuli via growth factors and neurotransmitter release. Brain-derived neurotrophic factor (BDNF), involved in synaptic maturation, activates Rac/RhoA-GEF proteins via TrkB tyrosine kinase (TrkB) receptors and induces spine head growth (Hale et al., 2011). During synaptic activation, glutamatergic transmission activates 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid receptor (AMPA) and N-Methyl-D-aspartic acid or N-Methyl-D-aspartate (NMDA) receptors and subsequently activates Rho proteins (Sin et al., 2002). Therefore, activity of the Rho proteins is sensitive to synaptic transmission and can regulate activity-induced maturation of the synapse. Synaptic maturation requires structurally modifying the synapse via cell-adhesion proteins including CNTNAP2, neuroligins 3 and 4, neurexin1, δ-catenin and associated Shank and Homer proteins which are frequently implicated in ASD (Tu et al., 1999; Sala et al., 2001; Jamain et al., 2003; Sudhof, 2008; Matter et al., 2009; Anderson et al., 2012). These proteins ensure proper synapse formation by bridging the pre- and postsynaptic sites, acting as a scaffold and stabilizing the cytoskeleton of the synapse (Kosik et al., 2005; Takeichi and Abe, 2005; Penagarikano and Geschwind, 2012). Since the Rho signaling pathways and synapse-spanning complexes are enriched with NDD-related proteins, they provide a direct link between NDDs and aberrant synapse development.


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

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

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.
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Related In: Results  -  Collection

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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.
Mentions: Initial stages of synapse formation and neuronal connectivity require modulation of the cytoskeletal F-actin via the Ras homologue subfamily of Rho GTPases. Many genes underlying monogenic NDDs interact directly with Rho signaling protein pathways. (Figure 1; Ramakers, 2002; Ethell and Pasquale, 2005). This family of small-GTPases includes ras homolog gene family, member A (RhoA), ras-related C3 botulinum toxin substrate (Rac1) and cell division cycle 42 (Cdc42), which dynamically regulate protrusion and retraction of spines via cytoskeletal actin remodelling (Tashiro et al., 2000; Ethell and Pasquale, 2005). Small guanosine-5'-triphosphate hydrolyzing enzymes (GTPases) typically cycle between active GTP-bound and inactive guanosine diphosphate- (GDP) bound states. These transitions are dynamically regulated by GTPase activating proteins (GAPs), guanine nucleotide exchange factors (GEFs), and by GDP dissociation inhibitors (GDI) inhibiting the conversion to the active GTP-bound state (Sasaki and Takai, 1998). In syndromic OPHN1 ID, changes in spine morphology are caused by the absence of OPHN1, a RhoA-GAP (Govek et al., 2004). The ID Williams syndrome is linked to the LIM domain kinase 1 (LIMK1) gene, whose product mediates changes in actin and spine morphology via Cdc42 and Rac1 pathways (Edwards et al., 1999). Additionally, LIMK1 interacts with P21-activated kinases (PAKs) which also harbor mutations in many nonsyndromic human ID cases (Allen and Walsh, 1999). Rho family members are activated by extracellular stimuli via growth factors and neurotransmitter release. Brain-derived neurotrophic factor (BDNF), involved in synaptic maturation, activates Rac/RhoA-GEF proteins via TrkB tyrosine kinase (TrkB) receptors and induces spine head growth (Hale et al., 2011). During synaptic activation, glutamatergic transmission activates 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid receptor (AMPA) and N-Methyl-D-aspartic acid or N-Methyl-D-aspartate (NMDA) receptors and subsequently activates Rho proteins (Sin et al., 2002). Therefore, activity of the Rho proteins is sensitive to synaptic transmission and can regulate activity-induced maturation of the synapse. Synaptic maturation requires structurally modifying the synapse via cell-adhesion proteins including CNTNAP2, neuroligins 3 and 4, neurexin1, δ-catenin and associated Shank and Homer proteins which are frequently implicated in ASD (Tu et al., 1999; Sala et al., 2001; Jamain et al., 2003; Sudhof, 2008; Matter et al., 2009; Anderson et al., 2012). These proteins ensure proper synapse formation by bridging the pre- and postsynaptic sites, acting as a scaffold and stabilizing the cytoskeleton of the synapse (Kosik et al., 2005; Takeichi and Abe, 2005; Penagarikano and Geschwind, 2012). Since the Rho signaling pathways and synapse-spanning complexes are enriched with NDD-related proteins, they provide a direct link between NDDs and aberrant synapse development.

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