- Email: [email protected]
KDM5C leads to GABA-related behavioral defects in C. elegans
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Abstracts / Int. J. Devl Neuroscience 47 (2015) 1–131
own fmr1 genotype, suggesting that maternal factors other than fmr1 transmission have substantial effects on offspring behavior. Here we asked whether the maternal genotype affects offspring social behavior, a phenotype of particular interest given its pervasiveness in numerous psychiatric conditions including autism spectrum disorder. We found that reduced maternal fmr1 expression was sufficient to induce altered social behaviors in both fmr1-/y (knockout; KO) and fmr1+/y (wildtype; WT) offspring, with WT animals exhibiting an intermediate level of enhanced approach and reduced avoidance behaviors. We observed no differences in olfactory discrimination, indicating that abnormal odorant cue processing is an unlikely cause of the observed social phenotype. To narrow down the developmental period sensitive to the maternal genotype effect, we crossfostered pups between WT and H females and found that exposure to either prenatal or postnatal H maternal environment is sufficient to induce the abnormal social phenotype. Furthermore, crossfostering to a postnatal WT environment fails to rescue the behavioral effect of a prenatal H maternal environment. Taken together, our data shows that the abnormal social phenotype, like hyperactivity, is dependent in part on the maternal fmr1 genotype and that this intergenerational effect is not mediated by genetic transmission. Although it is well established that prenatal and/or postnatal maternal factors including malnutrition, infections and stress can alter behaviors associated with autism and schizophrenia, additional studies are needed to identify the specific fmr1-associated maternal factor/s responsible for inducing the effects reported here. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.271 ISDN2014 0325 Lack of H3K4 demethylase rbr-2/KDM5C leads to GABA-related behavioral defects in C. elegans A.J. Rodrigues 1,2,3 , C. Bessa 1,2,∗,3 , F. Marques 1,2 , F. Pereira 1,2 , A. Amorim 1,2 , F. Lopes 1,2 , P. Maciel 1,2 1
University of Minho, Portugal ICVS/3B’s – PT Government Associate Laboratory, Portugal E-mail address: [email protected] (C. Bessa). 2
Intellectual disability (ID) is one of the most frequent and disabling neurological impairments with an estimated prevalence of 1.5–2% in Western countries. Technological advances such as the use of array comparative genomic hybridization (aCGH) and massive parallel sequencing have allowed the identification of novel genetic causes of ID. This large-scale analysis originates an incredible number of novel genetic associations that most often require functional validation. We are using the simple round worm Caenorhabditis elegans (C. elegans) as a platform to functionally validate ID genetic associations and to better understand the importance of target genes and proteins in the nervous system and neuronal function. So far, we have studied 35 mutant strains that correspond to 29 orthologues of human genes previously linked to ID. Absence of one candidate, rbr-2, the orthologue of human KDM5C/JARID1C, leads to anatomical reproductive defects, developmental delay (larval arrest), increased embryonic lethality and decreased life span. Interestingly, rbr-2 mutant worms also present several behavioural deficits which suggest an impairment of
3
Contributed equally to this work.
neuronal functions. Of notice, worms exhibit increased motor uncoordination and abnormal sensory chemotactic responses. By crossing the rbr-2 knock-out strain with reporter strains expressing GFP in specific neuronal sub-types, we found an increased occurrence of GABAergic network defects–namely abnormal neuronal process positioning and migration. In addition, these animals were more sensitive to Pentylenetetrazol (PTZ – a GABA antagonist) than wild-type worms. This correlates well with expression analysis of genes related to GABA metabolism or transport, some of which were found be altered in mutant worms. Overall, our data suggests that rbr-2, which encodes for a histone demethylase, plays a relevant role in nervous system development and specifically in GABA-dependent neuronal functions. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.272 ISDN2014 0326 Developmental trajectories of deep gray matter structures in healthy children and adults Marija Stosic 1 , Xu Han 1 , Muhammad Haque 1,4 , Laura Torres 2 , Jason Reynolds 2 , Amber Rogers 2 , Jeremy Jones 2 , Monica Proud 2 , Khader M. ´ Hasan 3 , Mirjana Maletic-Savati c´ 1,∗ 1 Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX, USA 2 Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA 3 The University of Texas Medical School at Houston, Houston, TX, USA E-mail address: [email protected] ´ ´ (M. Maletic-Savati c).
Human brain structure changes during aging and in pathological conditions. Understanding the trajectory of the anatomical alterations from early development to late adulthood in healthy humans provides an important foundation to interpret abnormalities seen in pathological conditions. Micro and macrostructural changes in the human brain can be captured using Magnetic Resonance Imaging (MRI), including diffusion tensor imaging (DTI) and high resolution T1-weighted imaging. The main goal of our study was to determine the MRI-based measures that accurately and sensitively predict temporal changes of the brain anatomy. In a cross-sectional study, we recruited 66 healthy subjects aged 245 years and measured three quantitative MRI-derived attributes, Intracranial volume-normalized volumes, fractional anisotropy (FA), and mean diffusivity (MD), in several grey matter structures (hippocampus, amygdala, caudate, putamen, pallidum, thalamus, accumbens) and lateral ventricle. Using an in-house developed algorithm, we integrated the information obtained from the DTI parameters, MD and FA, with the structural information detected by T1-weighted images. First, we found that each MRI-derived measure strongly correlated with age in three regions, hippocampus, amygdala and caudate. We then applied multivariate statistical modelling to quantify integrated imaging markers in all investigated brain regions over the life span. Interestingly, the same brain structures that showed correlation with age based on individual MRI measures, also contributed the most to age-separation when all MRI measures were integrated together. Overall, these results suggest that anatomical changes of selective brain regions are the
4 Current address: The University of Texas Medical School at Houston, Houston, TX, USA.
Abstracts / Int. J. Devl Neuroscience 47 (2015) 1–131
own fmr1 genotype, suggesting that maternal factors other than fmr1 transmission have substantial effects on offspring behavior. Here we asked whether the maternal genotype affects offspring social behavior, a phenotype of particular interest given its pervasiveness in numerous psychiatric conditions including autism spectrum disorder. We found that reduced maternal fmr1 expression was sufficient to induce altered social behaviors in both fmr1-/y (knockout; KO) and fmr1+/y (wildtype; WT) offspring, with WT animals exhibiting an intermediate level of enhanced approach and reduced avoidance behaviors. We observed no differences in olfactory discrimination, indicating that abnormal odorant cue processing is an unlikely cause of the observed social phenotype. To narrow down the developmental period sensitive to the maternal genotype effect, we crossfostered pups between WT and H females and found that exposure to either prenatal or postnatal H maternal environment is sufficient to induce the abnormal social phenotype. Furthermore, crossfostering to a postnatal WT environment fails to rescue the behavioral effect of a prenatal H maternal environment. Taken together, our data shows that the abnormal social phenotype, like hyperactivity, is dependent in part on the maternal fmr1 genotype and that this intergenerational effect is not mediated by genetic transmission. Although it is well established that prenatal and/or postnatal maternal factors including malnutrition, infections and stress can alter behaviors associated with autism and schizophrenia, additional studies are needed to identify the specific fmr1-associated maternal factor/s responsible for inducing the effects reported here. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.271 ISDN2014 0325 Lack of H3K4 demethylase rbr-2/KDM5C leads to GABA-related behavioral defects in C. elegans A.J. Rodrigues 1,2,3 , C. Bessa 1,2,∗,3 , F. Marques 1,2 , F. Pereira 1,2 , A. Amorim 1,2 , F. Lopes 1,2 , P. Maciel 1,2 1
University of Minho, Portugal ICVS/3B’s – PT Government Associate Laboratory, Portugal E-mail address: [email protected] (C. Bessa). 2
Intellectual disability (ID) is one of the most frequent and disabling neurological impairments with an estimated prevalence of 1.5–2% in Western countries. Technological advances such as the use of array comparative genomic hybridization (aCGH) and massive parallel sequencing have allowed the identification of novel genetic causes of ID. This large-scale analysis originates an incredible number of novel genetic associations that most often require functional validation. We are using the simple round worm Caenorhabditis elegans (C. elegans) as a platform to functionally validate ID genetic associations and to better understand the importance of target genes and proteins in the nervous system and neuronal function. So far, we have studied 35 mutant strains that correspond to 29 orthologues of human genes previously linked to ID. Absence of one candidate, rbr-2, the orthologue of human KDM5C/JARID1C, leads to anatomical reproductive defects, developmental delay (larval arrest), increased embryonic lethality and decreased life span. Interestingly, rbr-2 mutant worms also present several behavioural deficits which suggest an impairment of
3
Contributed equally to this work.
neuronal functions. Of notice, worms exhibit increased motor uncoordination and abnormal sensory chemotactic responses. By crossing the rbr-2 knock-out strain with reporter strains expressing GFP in specific neuronal sub-types, we found an increased occurrence of GABAergic network defects–namely abnormal neuronal process positioning and migration. In addition, these animals were more sensitive to Pentylenetetrazol (PTZ – a GABA antagonist) than wild-type worms. This correlates well with expression analysis of genes related to GABA metabolism or transport, some of which were found be altered in mutant worms. Overall, our data suggests that rbr-2, which encodes for a histone demethylase, plays a relevant role in nervous system development and specifically in GABA-dependent neuronal functions. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.272 ISDN2014 0326 Developmental trajectories of deep gray matter structures in healthy children and adults Marija Stosic 1 , Xu Han 1 , Muhammad Haque 1,4 , Laura Torres 2 , Jason Reynolds 2 , Amber Rogers 2 , Jeremy Jones 2 , Monica Proud 2 , Khader M. ´ Hasan 3 , Mirjana Maletic-Savati c´ 1,∗ 1 Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX, USA 2 Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA 3 The University of Texas Medical School at Houston, Houston, TX, USA E-mail address: [email protected] ´ ´ (M. Maletic-Savati c).
Human brain structure changes during aging and in pathological conditions. Understanding the trajectory of the anatomical alterations from early development to late adulthood in healthy humans provides an important foundation to interpret abnormalities seen in pathological conditions. Micro and macrostructural changes in the human brain can be captured using Magnetic Resonance Imaging (MRI), including diffusion tensor imaging (DTI) and high resolution T1-weighted imaging. The main goal of our study was to determine the MRI-based measures that accurately and sensitively predict temporal changes of the brain anatomy. In a cross-sectional study, we recruited 66 healthy subjects aged 245 years and measured three quantitative MRI-derived attributes, Intracranial volume-normalized volumes, fractional anisotropy (FA), and mean diffusivity (MD), in several grey matter structures (hippocampus, amygdala, caudate, putamen, pallidum, thalamus, accumbens) and lateral ventricle. Using an in-house developed algorithm, we integrated the information obtained from the DTI parameters, MD and FA, with the structural information detected by T1-weighted images. First, we found that each MRI-derived measure strongly correlated with age in three regions, hippocampus, amygdala and caudate. We then applied multivariate statistical modelling to quantify integrated imaging markers in all investigated brain regions over the life span. Interestingly, the same brain structures that showed correlation with age based on individual MRI measures, also contributed the most to age-separation when all MRI measures were integrated together. Overall, these results suggest that anatomical changes of selective brain regions are the
4 Current address: The University of Texas Medical School at Houston, Houston, TX, USA.