Meeting Report
Wiring the Brain: From Genetic to Neuronal Networks
April 21-24, 2009
Adare, County Limerick, Ireland
Organizers: Kevin Mitchell, Aiden Corvin, Isabella Graef, Edward Hubbard, Franck Polleux
April 21-24, 2009
Adare, County Limerick, Ireland
Organizers: Kevin Mitchell, Aiden Corvin, Isabella Graef, Edward Hubbard, Franck Polleux
Research over the past five years has shown that one of the systems impacted in autism appears to be brain connectivity. The need now is to understand exactly what mechanisms govern brain connectivity, and how those mechanisms may become damaged in autism. Therefore, Autism Speaks joined several other organizations in sponsoring the "Wiring the Brain" meeting, which took place April 21-24, in Adare Manor, Co. Limerick, and which brought together world-class researchers in developmental neurobiology, psychiatry, neurology, human genetics, systems and cognitive neuroscience. The aim was to foster communication between these often separate disciplines. Discussions centered on the topics of understanding the mechanisms that underlie brain wiring, how variation of genes critical for neural development affects neuronal connectivity and behavior, and how such variation can contribute to disease.
About 150 international delegates heard the latest research across multiple fields and saw the truly exciting progress in finding the links from development to function; from genotype to phenotype; from animals to humans; and from brain to mind. Autism highlights included the Keynote lecture by Daniel Geschwind, U.C. Los Angeles on "Autism: from Genes to Brain," which described the recent identification of genetic variants that increase autism risk and how researchers are characterizing their effects in humans. Most importantly for this conference, many of these genes are involved in specifying how nerve cells connect to each other. The questions discussed across the course of the meeting included: how do these genes normally work? Will we expect to find that single mutations in such genes cause most cases of autism? How do defects in formation of connections between nerve cells affect the function of neuronal networks? How does compromised network activity early in life affect individuals as they progress through development? Finally, how does this result in the specific spectrum of symptoms associated with autism?
These questions, along with many others, served to bring autism to the forefront of a major international meeting of researchers solving issues in brain connectivity.
In the conference opening day Keynote address from John Rubenstein, and in sessions on "Building the Brain" and "Making Connections," delegates heard the most recent research on the molecular and activity-dependent processes by which the brain is patterned, different cell types are specified, cellular migration into cortical layers (Fan Wang) and forebrain nuclei (Oscar Marin) is controlled (and connectivity is established over long (Alain Chedotal, Robert Hindges) and short ranges (Alex Kolodkin, Josh Huang). Many of the genes involved in these molecular processes, such as neurexins for example, are implicated directly in autism. Josh Huang described how neurexins are regulated by GABA-A-receptor signaling in an ongoing interplay between early specification and later activity-dependent refinement.
This theme was continued in the Keynote speech from Stanislas Dehaene who described how experience-dependent emergence of functionally specialized areas of the brain, such as those involved in reading, is subject to strong evolutionary, anatomical and developmental constraints. Organized circuits, hierarchies and maps are present early in infants and bias subsequent learning. Early defects in connectivity can thus have cascading effects by altering experience, which ultimately leads to very specific defects in particular psychological domains (Annette Karmiloff-Smith). Because of this, developmental disorders should not be conceptualized in the same way as adult disconnection syndromes caused by lesions or injury. In trying to understand the impact of particular mutations, it is crucial to keep developmental trajectories firmly in mind. A primary effect on eye movements, for example, could lead to downstream deficits in language acquisition (Karmiloff-Smith), while defects in cell migration can cause surprisingly specific effects on reading in developmental dyslexia (Al Galaburda).
The session on the "Genetic Architecture of Psychiatric and Neurological Disease" and the Keynote lecture by Daniel Geschwind highlighted a gradual shift in paradigm from one where disorders such as autism, schizophrenia and bipolar disorder are caused by a detrimental combination of genetic variants that are common in the population (a polygenic model) to one where individual cases are caused by single-gene mutations or copy number variants in many different genes (a heterogeneous model). Rapid advances in genomic and sequencing technology, described by Aiden Corvin, Mary-Claire King and Jacques Michaud, are already leading to the identification of many such rare, highly-penetrant alleles and revealing convergence on specific pathways involved in neural development, exemplified by DISC1 (Kirsty Millar). Many such mutations seem to predispose to psychiatric disease in general, with overlapping risk especially for autism, schizophrenia and bipolar disorder.
At the same time, genome-wide association studies have revealed a now-replicated role for some common variants as risk factors for disease (Corvin, Geschwind). Examples of how the effects of such variants could profitably be explored using intermediate cognitive or neuroimaging phenotypes were described by Geschwind, Andreas Meyer-Lindenberg and David Linden. Nevertheless, the total number of such common variants identified is much fewer than initially expected, and they collectively explain only a very small fraction of the overall disease heritability. A unifying model is that common variants may affect quantitative aspects of cognition in the general population and also act (more weakly in a statistical sense) as modifiers of the effects of rare, highly-penetrant variants.
Presentations across several sessions emphasized the point that the cellular complexity of the nervous system must be embraced to explain the emergent properties of neuronal networks. This complexity can now be harnessed using specific promoters to drive expression of transgenic markers or optogenetic tools to investigate the connectivity and development of specific cells and to control their activity in behaving animals. For example, studies of parvalbumin-positive (fast-spiking or basket) interneurons investigated the development of their connectivity (Josh Huang), and their pharmacological sensitivity in models of schizophrenia (Bita Moghaddam). These interneurons play a central role in synchronizing local networks at high frequencies, an essential aspect of information processing that correlates well with behavioral measures (Karl Deisseroth, Sean Hill). More generally, states of network arrhythmia were proposed as the underlying cause not just for epilepsy but also as factors contributing to the early cognitive decline in neurodegenerative disorders (Jeff Noebels) and could also explain many of the symptoms of schizophrenia (Danielle Bassett, Linden, Moghaddam).
Marius Wernig discussed the technology necessary to generate induced pluripotent stem (iPS) cells. He and Pierre Vanderhaeghen described how the detailed knowledge gleaned from decades of research into developmental pathways is now being applied to the differentiation of iPS or embryonic stem cells into highly specific cell types in vitro. The potential use of these approaches for transplantation therapies is already being explored, as is their obvious usefulness for research through the generation of patient-specific neurons in vitro. Stimulation of neurogenesis from endogenous neural stem cells is also an important potential therapeutic avenue that seems central to the action of some antidepressants. Hongjun Song described the generation and integration of young neurons and factors controlling epigenetic regulation in response to high levels of activity.
Probably the most important lesson from the meeting was that it will be essential to make connections across very different types of investigation if we are to fully explain how mutations in genes controlling neurodevelopmental processes can impact brain circuitry, and in ways that interact with ongoing experience to shape psychological faculties and sometimes lead to overt clinical dysfunction. A similar level of interdisciplinary discovery will also be required to translate findings from development to function, from genotype to phenotype, from cells to networks and from brain to mind.
The meeting was held in association with Neuroscience Ireland and Neuron (Cell Press) and with generous sponsorship from Science Foundation Ireland, the Wellcome Trust, the National Institute of Neurological Disorders and Stroke, Roche and Autism Speaks, as well as support from the Smurfit Institute of Genetics, Wings for Life, Wyeth, Lilly, the Trinity College Institute of Neuroscience, the Provost's Academic Development Fund, the Down Syndrome Research and Treatment Foundation, Genentech and Failte Ireland.
See www.wiringthebrain.com for more details.
About 150 international delegates heard the latest research across multiple fields and saw the truly exciting progress in finding the links from development to function; from genotype to phenotype; from animals to humans; and from brain to mind. Autism highlights included the Keynote lecture by Daniel Geschwind, U.C. Los Angeles on "Autism: from Genes to Brain," which described the recent identification of genetic variants that increase autism risk and how researchers are characterizing their effects in humans. Most importantly for this conference, many of these genes are involved in specifying how nerve cells connect to each other. The questions discussed across the course of the meeting included: how do these genes normally work? Will we expect to find that single mutations in such genes cause most cases of autism? How do defects in formation of connections between nerve cells affect the function of neuronal networks? How does compromised network activity early in life affect individuals as they progress through development? Finally, how does this result in the specific spectrum of symptoms associated with autism?
These questions, along with many others, served to bring autism to the forefront of a major international meeting of researchers solving issues in brain connectivity.
In the conference opening day Keynote address from John Rubenstein, and in sessions on "Building the Brain" and "Making Connections," delegates heard the most recent research on the molecular and activity-dependent processes by which the brain is patterned, different cell types are specified, cellular migration into cortical layers (Fan Wang) and forebrain nuclei (Oscar Marin) is controlled (and connectivity is established over long (Alain Chedotal, Robert Hindges) and short ranges (Alex Kolodkin, Josh Huang). Many of the genes involved in these molecular processes, such as neurexins for example, are implicated directly in autism. Josh Huang described how neurexins are regulated by GABA-A-receptor signaling in an ongoing interplay between early specification and later activity-dependent refinement.
This theme was continued in the Keynote speech from Stanislas Dehaene who described how experience-dependent emergence of functionally specialized areas of the brain, such as those involved in reading, is subject to strong evolutionary, anatomical and developmental constraints. Organized circuits, hierarchies and maps are present early in infants and bias subsequent learning. Early defects in connectivity can thus have cascading effects by altering experience, which ultimately leads to very specific defects in particular psychological domains (Annette Karmiloff-Smith). Because of this, developmental disorders should not be conceptualized in the same way as adult disconnection syndromes caused by lesions or injury. In trying to understand the impact of particular mutations, it is crucial to keep developmental trajectories firmly in mind. A primary effect on eye movements, for example, could lead to downstream deficits in language acquisition (Karmiloff-Smith), while defects in cell migration can cause surprisingly specific effects on reading in developmental dyslexia (Al Galaburda).
The session on the "Genetic Architecture of Psychiatric and Neurological Disease" and the Keynote lecture by Daniel Geschwind highlighted a gradual shift in paradigm from one where disorders such as autism, schizophrenia and bipolar disorder are caused by a detrimental combination of genetic variants that are common in the population (a polygenic model) to one where individual cases are caused by single-gene mutations or copy number variants in many different genes (a heterogeneous model). Rapid advances in genomic and sequencing technology, described by Aiden Corvin, Mary-Claire King and Jacques Michaud, are already leading to the identification of many such rare, highly-penetrant alleles and revealing convergence on specific pathways involved in neural development, exemplified by DISC1 (Kirsty Millar). Many such mutations seem to predispose to psychiatric disease in general, with overlapping risk especially for autism, schizophrenia and bipolar disorder.
At the same time, genome-wide association studies have revealed a now-replicated role for some common variants as risk factors for disease (Corvin, Geschwind). Examples of how the effects of such variants could profitably be explored using intermediate cognitive or neuroimaging phenotypes were described by Geschwind, Andreas Meyer-Lindenberg and David Linden. Nevertheless, the total number of such common variants identified is much fewer than initially expected, and they collectively explain only a very small fraction of the overall disease heritability. A unifying model is that common variants may affect quantitative aspects of cognition in the general population and also act (more weakly in a statistical sense) as modifiers of the effects of rare, highly-penetrant variants.
Presentations across several sessions emphasized the point that the cellular complexity of the nervous system must be embraced to explain the emergent properties of neuronal networks. This complexity can now be harnessed using specific promoters to drive expression of transgenic markers or optogenetic tools to investigate the connectivity and development of specific cells and to control their activity in behaving animals. For example, studies of parvalbumin-positive (fast-spiking or basket) interneurons investigated the development of their connectivity (Josh Huang), and their pharmacological sensitivity in models of schizophrenia (Bita Moghaddam). These interneurons play a central role in synchronizing local networks at high frequencies, an essential aspect of information processing that correlates well with behavioral measures (Karl Deisseroth, Sean Hill). More generally, states of network arrhythmia were proposed as the underlying cause not just for epilepsy but also as factors contributing to the early cognitive decline in neurodegenerative disorders (Jeff Noebels) and could also explain many of the symptoms of schizophrenia (Danielle Bassett, Linden, Moghaddam).
Marius Wernig discussed the technology necessary to generate induced pluripotent stem (iPS) cells. He and Pierre Vanderhaeghen described how the detailed knowledge gleaned from decades of research into developmental pathways is now being applied to the differentiation of iPS or embryonic stem cells into highly specific cell types in vitro. The potential use of these approaches for transplantation therapies is already being explored, as is their obvious usefulness for research through the generation of patient-specific neurons in vitro. Stimulation of neurogenesis from endogenous neural stem cells is also an important potential therapeutic avenue that seems central to the action of some antidepressants. Hongjun Song described the generation and integration of young neurons and factors controlling epigenetic regulation in response to high levels of activity.
Probably the most important lesson from the meeting was that it will be essential to make connections across very different types of investigation if we are to fully explain how mutations in genes controlling neurodevelopmental processes can impact brain circuitry, and in ways that interact with ongoing experience to shape psychological faculties and sometimes lead to overt clinical dysfunction. A similar level of interdisciplinary discovery will also be required to translate findings from development to function, from genotype to phenotype, from cells to networks and from brain to mind.
The meeting was held in association with Neuroscience Ireland and Neuron (Cell Press) and with generous sponsorship from Science Foundation Ireland, the Wellcome Trust, the National Institute of Neurological Disorders and Stroke, Roche and Autism Speaks, as well as support from the Smurfit Institute of Genetics, Wings for Life, Wyeth, Lilly, the Trinity College Institute of Neuroscience, the Provost's Academic Development Fund, the Down Syndrome Research and Treatment Foundation, Genentech and Failte Ireland.
See www.wiringthebrain.com for more details.
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