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PL.02.01 Neural mechanisms of risk for psychiatric disorders
S111
Plenary lectures
PL.02. ECNP Neuropsychopharmacology Award lecture 1 PL.02.01 Neural mechanisms of risk for psychiatric disorders A. Meyer-Lindenberg1 ° 1 University of Heidelberg, Zentralinstitut f¨ur Seelische Gesundheit, Department of Psychiatry and Psychotherapy, Heidelberg, Germany Many psychiatric disorders show subtle manifestations in brain structure and function and behavior long before a clinical diagnosis can currently be made. To move from symptomatic treatment to cure, recovery, and prevention, research must define these early stages of dysfunction to enable mechanism-based drug discovery and individualized psychotherapy. In this presentation, we discuss a research approach that focuses on mechanisms of risk − both genetic and environmental − as one strategy to move the field closer to these translational goals. Using schizophrenia as an example, we discuss work that shows a convergent impact of both genetic and environmental risk factors on core neural circuits involved in the regulation of limbic structures, especially ventral striatum, amygdala, and hippocampus, by areas in prefrontal cortex, both lateral and medial. Strategies to further dissect the molecular and cellular contributions to these “risk mechanisms” are discussed. We argue that this approach begins to highlight transdiagnostic, clinically relevant systems that should be a focus of treatment development and individualization. We indicate strategic interactions between academic and industrial research suggested by these risk mechanisms, such as back-translated animal models and earlyphase human mechanistic studies.
PL.03. ECNP Neuropsychopharmacology Award lecture 2 PL.03.01 Schizophrenia: from pathophysiological understanding to novel treatments P.J. Harrison1 ° 1 University of Oxford, Neuroscience Building Department of Psychiatry Warneford Hospital, Oxford, United Kingdom A wide range of novel targets for the treatment of the psychotic and cognitive symptoms of schizophrenia are currently under investigation. Their number and diversity − and the slow progress to date − attest to the complexity of the therapeutic challenges involved. These considerations in turn require that all available research strategies and techniques are brought to bear upon the problem. Amongst these, this lecture will consider how neurobiological studies of schizophrenia itself − in conjunction with experimental models thereof − can contribute to the identification
and advancement of novel targets. Such studies include neurochemistry, neuropathology, neuroimaging, and genetics. These aspects of the schizophrenia disease process contribute differentially to the evaluation of different targets. For example, the rationale for glutamatergic N-methyl-D-aspartate (NMDA) receptor-based approaches to schizophrenia therapy finds support from all these domains, but the specific case for D-amino acid oxidase (DAO) inhibitors is strengthened by findings that activity of the enzyme is increased in the disorder. A different balance of factors underlies the interest in catechol-O-methyl transferase (COMT) inhibitors, for which genetic and functional imaging considerations predominate, against the backdrop of established dopaminergic involvement in the disease process. The lecture will illustrate these issues with reference to the drugs and targets mentioned above, amongst others. It will also consider more broadly how recent developments in the pathophysiological understanding of schizophrenia can be integrated with data from preclinical studies, and with theoretical models, in order to foster psychopharmacological advances. Disclosure statement: In the past three years, I have received an unrestricted educational grant from Takeda, and have received speaker or consultancy fees from AstraZeneca, Janssen, Merck, Otsuka and Takeda.
PL.06. Plenary lecture PL.06.01 Opioid systems: probing molecular processes of brain function B.L. Kieffer1 ° , C. Gav´eriaux-Ruff1 1 Institut de G´en´etique et de Biologie Mol´eculaire et Cellulaire, CNRS/INSERM/ULP, Illkirch Cedex, France Molecular processes underlying brain function, plasticity and disease are highly complex. These operate within specific compartments of neuronal cells, and translate at systems level through neuronal connectivity in highly organized neural circuits. Probing molecular events in high-order responses, and understanding their relevance to brain activity requires the development of targeted manipulations that ultimately impact on neuronal function in vivo, and possibly behavior. Genetic approaches have been instrumental towards these aims [1], and the opioid system has proved to be a pioneer model system in the development of gene targeting approaches in mice. Opiates have been used since thousand years for their pain-relieving and rewarding properties. These compounds produce their potent effects by activating opioid receptors in the brain, thereby highjacking a complex neuromodulatory system that includes three receptors (mu, delta and kappa) normally stimulated by endogenous peptides. The presentation will focus on this fascinating and complex neuromodulatory system, which controls sensory modalities (pain) and emotional state or responses (euphoria, dysphoria, stress). Targeted mutagenesis in mice has allowed demonstrating the distinct role of each receptor in behavioral responses, identifying yet unreported roles for these “old” receptors, discovering novel gene targets for psychiatric research and visualizing receptor trafficking in live neurons for the
Plenary lectures
PL.02. ECNP Neuropsychopharmacology Award lecture 1 PL.02.01 Neural mechanisms of risk for psychiatric disorders A. Meyer-Lindenberg1 ° 1 University of Heidelberg, Zentralinstitut f¨ur Seelische Gesundheit, Department of Psychiatry and Psychotherapy, Heidelberg, Germany Many psychiatric disorders show subtle manifestations in brain structure and function and behavior long before a clinical diagnosis can currently be made. To move from symptomatic treatment to cure, recovery, and prevention, research must define these early stages of dysfunction to enable mechanism-based drug discovery and individualized psychotherapy. In this presentation, we discuss a research approach that focuses on mechanisms of risk − both genetic and environmental − as one strategy to move the field closer to these translational goals. Using schizophrenia as an example, we discuss work that shows a convergent impact of both genetic and environmental risk factors on core neural circuits involved in the regulation of limbic structures, especially ventral striatum, amygdala, and hippocampus, by areas in prefrontal cortex, both lateral and medial. Strategies to further dissect the molecular and cellular contributions to these “risk mechanisms” are discussed. We argue that this approach begins to highlight transdiagnostic, clinically relevant systems that should be a focus of treatment development and individualization. We indicate strategic interactions between academic and industrial research suggested by these risk mechanisms, such as back-translated animal models and earlyphase human mechanistic studies.
PL.03. ECNP Neuropsychopharmacology Award lecture 2 PL.03.01 Schizophrenia: from pathophysiological understanding to novel treatments P.J. Harrison1 ° 1 University of Oxford, Neuroscience Building Department of Psychiatry Warneford Hospital, Oxford, United Kingdom A wide range of novel targets for the treatment of the psychotic and cognitive symptoms of schizophrenia are currently under investigation. Their number and diversity − and the slow progress to date − attest to the complexity of the therapeutic challenges involved. These considerations in turn require that all available research strategies and techniques are brought to bear upon the problem. Amongst these, this lecture will consider how neurobiological studies of schizophrenia itself − in conjunction with experimental models thereof − can contribute to the identification
and advancement of novel targets. Such studies include neurochemistry, neuropathology, neuroimaging, and genetics. These aspects of the schizophrenia disease process contribute differentially to the evaluation of different targets. For example, the rationale for glutamatergic N-methyl-D-aspartate (NMDA) receptor-based approaches to schizophrenia therapy finds support from all these domains, but the specific case for D-amino acid oxidase (DAO) inhibitors is strengthened by findings that activity of the enzyme is increased in the disorder. A different balance of factors underlies the interest in catechol-O-methyl transferase (COMT) inhibitors, for which genetic and functional imaging considerations predominate, against the backdrop of established dopaminergic involvement in the disease process. The lecture will illustrate these issues with reference to the drugs and targets mentioned above, amongst others. It will also consider more broadly how recent developments in the pathophysiological understanding of schizophrenia can be integrated with data from preclinical studies, and with theoretical models, in order to foster psychopharmacological advances. Disclosure statement: In the past three years, I have received an unrestricted educational grant from Takeda, and have received speaker or consultancy fees from AstraZeneca, Janssen, Merck, Otsuka and Takeda.
PL.06. Plenary lecture PL.06.01 Opioid systems: probing molecular processes of brain function B.L. Kieffer1 ° , C. Gav´eriaux-Ruff1 1 Institut de G´en´etique et de Biologie Mol´eculaire et Cellulaire, CNRS/INSERM/ULP, Illkirch Cedex, France Molecular processes underlying brain function, plasticity and disease are highly complex. These operate within specific compartments of neuronal cells, and translate at systems level through neuronal connectivity in highly organized neural circuits. Probing molecular events in high-order responses, and understanding their relevance to brain activity requires the development of targeted manipulations that ultimately impact on neuronal function in vivo, and possibly behavior. Genetic approaches have been instrumental towards these aims [1], and the opioid system has proved to be a pioneer model system in the development of gene targeting approaches in mice. Opiates have been used since thousand years for their pain-relieving and rewarding properties. These compounds produce their potent effects by activating opioid receptors in the brain, thereby highjacking a complex neuromodulatory system that includes three receptors (mu, delta and kappa) normally stimulated by endogenous peptides. The presentation will focus on this fascinating and complex neuromodulatory system, which controls sensory modalities (pain) and emotional state or responses (euphoria, dysphoria, stress). Targeted mutagenesis in mice has allowed demonstrating the distinct role of each receptor in behavioral responses, identifying yet unreported roles for these “old” receptors, discovering novel gene targets for psychiatric research and visualizing receptor trafficking in live neurons for the