- Email: [email protected]
37.2 INFLAMMATORY MEDIATORS OF PRENATAL STRESS EFFECTS ON NEURODEVELOPMENT
SYMPOSIA 37.0 – 37.3
SYMPOSIUM 37 ANIMAL MODELS FOR CHILD AND ADOLESCENT PSYCHIATRY Paul E. Glaser, MD, PhD, Washington Univ. in St. Louis, Dept. of Psychiatry, 660 S. Euclid Ave, Saint Louis, MO 63110; Hanna Stevens, MD, PhD, University of Iowa, 169 Newton Rd, 1330 PBDB, Iowa City, IA 52246; Paul E. Glaser, MD, PhD Objectives: Animal models continue to contribute to a new understanding and potential new treatments for child and adolescent psychiatric disorders. This forum provides a way to bring translatable scientific findings from highly respected scientific investigators to clinicians and clinicianscientists. Methods: Model systems from Drosophila to primates will be presented. A variety of approaches will be used that shed light on several important questions as follows. 1) What are the roles that gene variants, identified in children with psychiatric disorders, play in the nervous system? 2) How do known risk factors for childhood psychiatric disorders affect brain development and functioning? 3) How do neural systems identified in animals inform the development of treatments? Results: This Symposium will briefly review the scope of animal research and recent contributions to child psychiatry. It will then specifically address the following: 1) the use of rodent models determining the effects of maternal stress in utero and inflammatory mediators on the developing brain; 2) the investigation of Fragile X in rodent models and how understanding a specific glutamate receptor could lead to novel therapeutics; 3) primate investigations into the nature of childhood depression and suicide; and 4) how a mouse model with altered histamine regulation leads to a model for TD. Conclusions: The ultimate goal of all of these areas of investigation is to understand the underpinnings of psychiatric disorders more deeply to improve outcomes in children and adolescents by developing better diagnosis, prevention, and treatment.
ANI NEURODEV R http://dx.doi.org/10.1016/j.jaac.2016.07.333
37.1 INTRODUCTION: HOW ANIMAL MODELS INFORM CHILD AND ADOLESCENT PSYCHIATRY Sunil Q. Mehta, MD, PhD, University of California, Los Angeles, 760 Westwood Plaza, Rm 47-429B, Los Angeles, CA 90024 Objectives: Historically, animal models of psychiatric disorders have provided insight into the mechanisms of psychiatric disorders. Animal models have been critical in developing new therapeutics for child and adolescent disorders. Methods: A brief description of the range of animal models will be given. Specific focus on the Drosophila model will demonstrate how it contributes to our understanding of the genetic contributions to conditions such as ASD. Results: Animal models have yielded an understanding to the importance of genes and gene environment interactions. Conclusions: As genome-wide association studies yield more target genes and sets of genes, animal models will be essential to help entangle the role of these genes, describe their function leading to disease, and give us clues to developing new treatments.
GS http://dx.doi.org/10.1016/j.jaac.2016.07.334
37.2 INFLAMMATORY MEDIATORS OF PRENATAL STRESS EFFECTS ON NEURODEVELOPMENT Hanna Stevens, MD, PhD, University of Iowa, 169 Newton Rd., 1330 PBDB, Iowa City, IA 52246 Objectives: Prenatal stress (PS) is a risk factor for neuropsychiatric illness and alterations in cognitive and emotional development in children and adolescents. In animal models, PS results in persistent changes in behavior
S316
www.jaacap.org
and neural functioning, allowing the mechanisms to be examined. By understanding what maternal factors are critical for the impact on offspring, preventive measures to buffer stress factors could be developed. Methods: We examined offspring following repetitive prenatal restraint stress or repetitive maternal prenatal exposure to corticosterone, interleukin-6 (IL-6), and interleukin-1b (IL-1b). We assessed cellular and molecular markers of GABAergic cell development and the morphology of cells expressing Iba1-embyronic microglia. Blockade of the proinflammatory mediator IL-6 was tested with repetitive maternal exposure to neutralizing IL6 antibody and examination of brain development of offspring and adult anxiety-like behavior. Results: The migration of GAD67 GFP+ inhibitory neuron progenitors was restricted initially after one day of exposure by PS, corticosterone, and both cytokines; however, this effect persisted only in prenatally stressed and IL-6exposed offspring. Cytokine-exposed embryos showed some similar effects on GABAergic progenitor gene expression as found with PS. PS exposure resulted in a higher density of Iba1+ microglia with a phagocytosing morphology. This was also found in IL-6-exposed embryonic brain. Blockade of IL-6 signaling by anti–IL-6 antibody injection during PS normalized the morphology of Iba1+ cells in embryonic cortical plate. However, migration deficits of GABAergic progenitors with PS were not normalized by anti-IL-6 antibody. Likewise, behavioral changes in adult animals after PS were not rescued by anti-IL-6 antibody. Conclusions: PS may exert some developmental effects through inflammatory mediators, including IL-6. This work demonstrates that inflammatory systems, including microglia and cytokines, which have an increasingly recognized role in the pathophysiology of neuropsychiatric disorders, are among the mechanisms by which PS increases the risk for these illnesses.
R http://dx.doi.org/10.1016/j.jaac.2016.07.335
37.3 THE ROLE OF METABOTROPIC GLUTAMATE RECEPTOR 5 IN FRAGILE X SYNDROME: FROM MICE TO MEN Karen O’Malley, PhD, Neuroscience, Washington University in St. Louis, 660 S. Euclid Ave., St. Louis, MO 63110 Objectives: Fragile X syndrome (FXS), the most common form of inherited intellectual disability and ASD, is thought, in part, to be a disorder of misregulated synaptogenesis. Enriched in postsynaptic dendrites, the fragile X intellectual disability (FMR1) gene encodes a protein, fragile X intellectual disability protein (FMRP), which is thought to function as a translational repressor of mRNAs involved in synaptic plasticity. Methods: We have observed mice neuronal systems and human embryonic kidney cell lines (HEK293 cells) in culture to study the function of mGluR5 receptors. New pharmacological and genetic data show that FMRP is a key regulator of metabotropic glutamate receptor, mGluR5-dependent synaptic plasticity, serving to oppose mGluR5 function. Thus, activation of mGluR5 initiates signaling pathways that are normally kept in check by the suppressive actions of FMRP. Results: It is not unexpected that we have shown that activation of mGluR5 located on the cell surface or on intracellular membranes, where it is highly expressed (>80–90 percent), gives rise to distinct Ca2+ responses that, in turn, lead to unique signaling cascades. Because most studies examining mGluR5-mediated synaptic plasticity and FMRP function have relied on the mGluR5 agonist, DHPG, which we have shown only activates cell surface receptors, the question arises whether a large proportion of mGluR5 responses are being missed. To address this critical issue, we are dissecting receptor-specific contributions to the signaling mechanisms underlying mGluR5-dependent synaptic plasticity. Conclusions: We are also testing various negative allosteric modulators to determine whether differential inactivation of receptors might underlie recent clinical outcomes. Future studies targeting drugs to cell surface versus intracellular receptors might lead to new therapeutic tools for these diseases.
NEURODEV http://dx.doi.org/10.1016/j.jaac.2016.07.336
J OURNAL
OF THE
AMERICAN ACADEMY OF CHILD & ADOLESCENT P SYCHIATRY VOLUME 55 NUMBER 10S OCTOBER 2016
SYMPOSIUM 37 ANIMAL MODELS FOR CHILD AND ADOLESCENT PSYCHIATRY Paul E. Glaser, MD, PhD, Washington Univ. in St. Louis, Dept. of Psychiatry, 660 S. Euclid Ave, Saint Louis, MO 63110; Hanna Stevens, MD, PhD, University of Iowa, 169 Newton Rd, 1330 PBDB, Iowa City, IA 52246; Paul E. Glaser, MD, PhD Objectives: Animal models continue to contribute to a new understanding and potential new treatments for child and adolescent psychiatric disorders. This forum provides a way to bring translatable scientific findings from highly respected scientific investigators to clinicians and clinicianscientists. Methods: Model systems from Drosophila to primates will be presented. A variety of approaches will be used that shed light on several important questions as follows. 1) What are the roles that gene variants, identified in children with psychiatric disorders, play in the nervous system? 2) How do known risk factors for childhood psychiatric disorders affect brain development and functioning? 3) How do neural systems identified in animals inform the development of treatments? Results: This Symposium will briefly review the scope of animal research and recent contributions to child psychiatry. It will then specifically address the following: 1) the use of rodent models determining the effects of maternal stress in utero and inflammatory mediators on the developing brain; 2) the investigation of Fragile X in rodent models and how understanding a specific glutamate receptor could lead to novel therapeutics; 3) primate investigations into the nature of childhood depression and suicide; and 4) how a mouse model with altered histamine regulation leads to a model for TD. Conclusions: The ultimate goal of all of these areas of investigation is to understand the underpinnings of psychiatric disorders more deeply to improve outcomes in children and adolescents by developing better diagnosis, prevention, and treatment.
ANI NEURODEV R http://dx.doi.org/10.1016/j.jaac.2016.07.333
37.1 INTRODUCTION: HOW ANIMAL MODELS INFORM CHILD AND ADOLESCENT PSYCHIATRY Sunil Q. Mehta, MD, PhD, University of California, Los Angeles, 760 Westwood Plaza, Rm 47-429B, Los Angeles, CA 90024 Objectives: Historically, animal models of psychiatric disorders have provided insight into the mechanisms of psychiatric disorders. Animal models have been critical in developing new therapeutics for child and adolescent disorders. Methods: A brief description of the range of animal models will be given. Specific focus on the Drosophila model will demonstrate how it contributes to our understanding of the genetic contributions to conditions such as ASD. Results: Animal models have yielded an understanding to the importance of genes and gene environment interactions. Conclusions: As genome-wide association studies yield more target genes and sets of genes, animal models will be essential to help entangle the role of these genes, describe their function leading to disease, and give us clues to developing new treatments.
GS http://dx.doi.org/10.1016/j.jaac.2016.07.334
37.2 INFLAMMATORY MEDIATORS OF PRENATAL STRESS EFFECTS ON NEURODEVELOPMENT Hanna Stevens, MD, PhD, University of Iowa, 169 Newton Rd., 1330 PBDB, Iowa City, IA 52246 Objectives: Prenatal stress (PS) is a risk factor for neuropsychiatric illness and alterations in cognitive and emotional development in children and adolescents. In animal models, PS results in persistent changes in behavior
S316
www.jaacap.org
and neural functioning, allowing the mechanisms to be examined. By understanding what maternal factors are critical for the impact on offspring, preventive measures to buffer stress factors could be developed. Methods: We examined offspring following repetitive prenatal restraint stress or repetitive maternal prenatal exposure to corticosterone, interleukin-6 (IL-6), and interleukin-1b (IL-1b). We assessed cellular and molecular markers of GABAergic cell development and the morphology of cells expressing Iba1-embyronic microglia. Blockade of the proinflammatory mediator IL-6 was tested with repetitive maternal exposure to neutralizing IL6 antibody and examination of brain development of offspring and adult anxiety-like behavior. Results: The migration of GAD67 GFP+ inhibitory neuron progenitors was restricted initially after one day of exposure by PS, corticosterone, and both cytokines; however, this effect persisted only in prenatally stressed and IL-6exposed offspring. Cytokine-exposed embryos showed some similar effects on GABAergic progenitor gene expression as found with PS. PS exposure resulted in a higher density of Iba1+ microglia with a phagocytosing morphology. This was also found in IL-6-exposed embryonic brain. Blockade of IL-6 signaling by anti–IL-6 antibody injection during PS normalized the morphology of Iba1+ cells in embryonic cortical plate. However, migration deficits of GABAergic progenitors with PS were not normalized by anti-IL-6 antibody. Likewise, behavioral changes in adult animals after PS were not rescued by anti-IL-6 antibody. Conclusions: PS may exert some developmental effects through inflammatory mediators, including IL-6. This work demonstrates that inflammatory systems, including microglia and cytokines, which have an increasingly recognized role in the pathophysiology of neuropsychiatric disorders, are among the mechanisms by which PS increases the risk for these illnesses.
R http://dx.doi.org/10.1016/j.jaac.2016.07.335
37.3 THE ROLE OF METABOTROPIC GLUTAMATE RECEPTOR 5 IN FRAGILE X SYNDROME: FROM MICE TO MEN Karen O’Malley, PhD, Neuroscience, Washington University in St. Louis, 660 S. Euclid Ave., St. Louis, MO 63110 Objectives: Fragile X syndrome (FXS), the most common form of inherited intellectual disability and ASD, is thought, in part, to be a disorder of misregulated synaptogenesis. Enriched in postsynaptic dendrites, the fragile X intellectual disability (FMR1) gene encodes a protein, fragile X intellectual disability protein (FMRP), which is thought to function as a translational repressor of mRNAs involved in synaptic plasticity. Methods: We have observed mice neuronal systems and human embryonic kidney cell lines (HEK293 cells) in culture to study the function of mGluR5 receptors. New pharmacological and genetic data show that FMRP is a key regulator of metabotropic glutamate receptor, mGluR5-dependent synaptic plasticity, serving to oppose mGluR5 function. Thus, activation of mGluR5 initiates signaling pathways that are normally kept in check by the suppressive actions of FMRP. Results: It is not unexpected that we have shown that activation of mGluR5 located on the cell surface or on intracellular membranes, where it is highly expressed (>80–90 percent), gives rise to distinct Ca2+ responses that, in turn, lead to unique signaling cascades. Because most studies examining mGluR5-mediated synaptic plasticity and FMRP function have relied on the mGluR5 agonist, DHPG, which we have shown only activates cell surface receptors, the question arises whether a large proportion of mGluR5 responses are being missed. To address this critical issue, we are dissecting receptor-specific contributions to the signaling mechanisms underlying mGluR5-dependent synaptic plasticity. Conclusions: We are also testing various negative allosteric modulators to determine whether differential inactivation of receptors might underlie recent clinical outcomes. Future studies targeting drugs to cell surface versus intracellular receptors might lead to new therapeutic tools for these diseases.
NEURODEV http://dx.doi.org/10.1016/j.jaac.2016.07.336
J OURNAL
OF THE
AMERICAN ACADEMY OF CHILD & ADOLESCENT P SYCHIATRY VOLUME 55 NUMBER 10S OCTOBER 2016