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The emerging neuroscience of autism spectrum disorders
B RA IN RE S EA R CH 1 38 0 (2 0 1 1 ) 1 – 2
available at www.sciencedirect.com
www.elsevier.com/locate/brainres
Editorial
The emerging neuroscience of autism spectrum disorders On November 11th and 12th, 2010, a satellite symposium to the annual meeting of the Society for Neuroscience was held in San Diego, California, focusing on the emerging neuroscience of autism spectrum disorders (ASDs). This symposium discussed all major aspects of ASDs and attracted over 250 participants. There were eight themes to the meeting from phenotype and diagnostics all the way through to behavioral and pharmacological interventions, and including many sessions of particular interest to neuroscientists. All of the speakers prepared a manuscript related to their presentation found in this special issue of Brain Research, and Dr. David Amaral of the M.I.N.D. Institute and UC Davis provided a detailed summary of the talks and the symposium, which can also be found in the current issue. In this introduction, we highlight two themes of perhaps particular interest to neuroscientists new to autism, who are trying to integrate the many reports in the field today.
Genetics and genomics of autism spectrum disorders After a welcome by Dr. Joseph Buxbaum, of Mount Sinai School of Medicine and Chair of the Organizing Committee, the first session began with a focus on the genetic and genomic architecture of ASDs. Dr. Catalina Betancur (INSERM, Paris, France) summarized the evidence that ASDs are highly genetic disorders and showed compelling data for the profound etiological heterogeneity in ASDs. Dr. Betancur pointed out the ASDs are behaviorally diagnosed, but through careful clinical genetic analyses, well more than 10% of patients can be given an etiological diagnosis, including one of as many as 100 or more chromosomal abnormalities and known genetic disorders. These diverse causes of ASDs are associated with high risk for the disorder. Dr. Stephen Scherer (University of Toronto) extended the discussion on genetic causes of ASDs by highlighting the emerging evidence for inherited and de novo copy number variation (CNV) in ASDs. Dr. Scherer pointed out the ubiquity of CNV in the human genome and also pointed out the variable expressivity that may be associated with certain CNV. CNV at NRXN1 shows very high odds ratios for a neuropsychiatric phenotype (cited as ~16-fold by Dr. Scherer) but the phenotypes include ASDs, intellectual disability (ID), schizophrenia and bipolar disorder. What factors determine presentation need to be determined. In the case of the X-
linked PTCDH1 gene, Dr. Scherer suggested that mutation of the coding region may be more closely associated with ID, mutation of the antisense transcript may be more closely associated with higher functioning ASD, and mutation of both may be more closely associated with lower functioning ASD. Dr. Bernie Devlin (University of Pittsburgh) summarized the three published genome-wide association studies and made the point that main findings from each were not clearly replicated in the others. This led him to define the boundaries of likely common (SNP) variants that might have remained as yet undiscovered, and he showed that the current results almost certainly exclude any SNPs with an odds ratio of above 1.7 and probably exclude SNPs with an odds ratio above 1.2. This indicates that many, and even most, of the candidate gene association studies reported to date are likely to be falsepositive findings and that until sample sizes in ASD research reach those in other complex disorders such as schizophrenia, there is not sufficient power to reliably detect common variants of week effect contributing to ASD risk. Dr. Buxbaum finished the session with an overview of the methods of high-throughput (“next-generation”) sequencing and summarized the ongoing large-scale whole-exome sequencing being carried out in ASDs. Dr. Buxbaum, together with Dr. Devlin and others, is part of a multi-site study to complete whole-exome sequencing in 1000 ASD cases and 1000 matched controls as a means to identify additional risk loci for ASD. Dr. Scherer heads a similar independent effort. Given the likelihood that a significant proportion of ASD is the results of rare variants of major effect (as discussed by Drs. Betancur and Scherer), these approaches hold great promise to bring us to the post-discovery era in ASD enomics.
Imaging in autism spectrum disorders Much has been said about the limiting amount of very high quality postmortem tissue available in ASDs. This deficit, which is being addressed by many of the advocacy groups including Autism Speaks, is in part balanced by the exceptional, careful structural and functional imaging studies going on. The careful reader will however have recognized that many imaging studies are being carried out on higher functioning subjects, although several sites, including the M. I.N.D. Institute/UC Davis and UC San Diego, have developed protocols suitable for more representative groups of subjects.
2
B RA IN RE S EAR CH 1 38 0 (2 0 1 1) 1 – 2
A recurrent theme during the meeting was the notion of early brain overgrowth in subject with autism, which has been documented in many ways, from simple biometric measurement of head circumference, brain structural imaging, as well as neuropathologically using quantitative tools (Dr. Eric Couchesne, UCSD). Several speakers discussed the need to understand in detail the deficits in cortical connectivity that reflect the existence of areas of abnormal cortical activation or cortical specialization. Recent studies involving structural studies of grey and white matter integrity in autism, as well as functional imaging of cortical networks, have demonstrated a certain degree of underconnectivity in distributed network in ASDs as well as deficit in the default mode network during resting state (Dr. Kimberly Stigler, Indiana University). Using self-organizing maps to calculate connectivity, Dr. Catherine Lord (University of Michigan) showed that adolescent with ASDs have a weaker connectivity between the posterior hub of the default network and the superior frontal cortex compared to controls. Such functional alterations are in turn fully compatible with an emerging number of rigorous neuropathological analyses that demonstrate abnormal numbers of neurons in discrete brain territories, such as the lateral amygdala (Drs. Cyndi Schumann and David Amaral, UC Davis), or in the fusiform face area and frontoinsular cortex (Dr. Hof). These converging data point to the need to develop novel methodologies to assess such discrete functional and anatomical changes across the entire lifespan as some manifestations of ASDs are likely to vary considerably during development. In this context, Dr. Karen Pierce (UCSD) eloquently presented new data obtained in very young children using sleep fMRI, and discussed the potential of this approach for early diagnosis and biomarker discovery. The relatively circumscribed – and variable – neuropathological changes seen in ASD patients will require a deeper analysis at the single cell level. While much can be done in animal models, a molecular analysis of postmortem neuro-
pathological materials remains crucial. Dr. Gene Blatt, from Boston University, presented evidence for disruption of inhibitory neurotransmission in the fusiform gyrus and posterior cingulate cortex, using ligand-binding autoradiography, revealing imbalances in GABA and benzodiazepine receptors numbers and affinity in ASD, which could be directly related to the behavioral and social core disturbances that characterize patients with ASDs.
Conclusions Altogether the symposium was distinguished by a series of excellent presentations and we are very grateful to the speakers who were willing to give of their time to present new and exciting data. We are also very grateful to the participants, both for their engaging questions and for the 100 posters that were presented at the meeting. In addition, we appreciate the anonymous reviewers and, in particular, we appreciate the unstinting help of Dr. Catalina Betancur who took the lead on organizing the review of all abstracts. Finally, we appreciate the ongoing input from all the members of the Organizing Committee (Drs. Bloom, Sharp, Amaral, and Courchesne), and Dr. Paul Carton and the staff of Elsevier and Brain Research. This symposium was a year in the making, and thanks to all of these people and to all of the speakers, it was, in our opinion, a great success.
Joseph D. Buxbaum Patrick R. Hof Mount Sinai School of Medicine, New York, NY, USA 0006-8993/$ – see front matter © 2011 Published by Elsevier B.V. doi:10.1016/j.brainres.2011.02.030
available at www.sciencedirect.com
www.elsevier.com/locate/brainres
Editorial
The emerging neuroscience of autism spectrum disorders On November 11th and 12th, 2010, a satellite symposium to the annual meeting of the Society for Neuroscience was held in San Diego, California, focusing on the emerging neuroscience of autism spectrum disorders (ASDs). This symposium discussed all major aspects of ASDs and attracted over 250 participants. There were eight themes to the meeting from phenotype and diagnostics all the way through to behavioral and pharmacological interventions, and including many sessions of particular interest to neuroscientists. All of the speakers prepared a manuscript related to their presentation found in this special issue of Brain Research, and Dr. David Amaral of the M.I.N.D. Institute and UC Davis provided a detailed summary of the talks and the symposium, which can also be found in the current issue. In this introduction, we highlight two themes of perhaps particular interest to neuroscientists new to autism, who are trying to integrate the many reports in the field today.
Genetics and genomics of autism spectrum disorders After a welcome by Dr. Joseph Buxbaum, of Mount Sinai School of Medicine and Chair of the Organizing Committee, the first session began with a focus on the genetic and genomic architecture of ASDs. Dr. Catalina Betancur (INSERM, Paris, France) summarized the evidence that ASDs are highly genetic disorders and showed compelling data for the profound etiological heterogeneity in ASDs. Dr. Betancur pointed out the ASDs are behaviorally diagnosed, but through careful clinical genetic analyses, well more than 10% of patients can be given an etiological diagnosis, including one of as many as 100 or more chromosomal abnormalities and known genetic disorders. These diverse causes of ASDs are associated with high risk for the disorder. Dr. Stephen Scherer (University of Toronto) extended the discussion on genetic causes of ASDs by highlighting the emerging evidence for inherited and de novo copy number variation (CNV) in ASDs. Dr. Scherer pointed out the ubiquity of CNV in the human genome and also pointed out the variable expressivity that may be associated with certain CNV. CNV at NRXN1 shows very high odds ratios for a neuropsychiatric phenotype (cited as ~16-fold by Dr. Scherer) but the phenotypes include ASDs, intellectual disability (ID), schizophrenia and bipolar disorder. What factors determine presentation need to be determined. In the case of the X-
linked PTCDH1 gene, Dr. Scherer suggested that mutation of the coding region may be more closely associated with ID, mutation of the antisense transcript may be more closely associated with higher functioning ASD, and mutation of both may be more closely associated with lower functioning ASD. Dr. Bernie Devlin (University of Pittsburgh) summarized the three published genome-wide association studies and made the point that main findings from each were not clearly replicated in the others. This led him to define the boundaries of likely common (SNP) variants that might have remained as yet undiscovered, and he showed that the current results almost certainly exclude any SNPs with an odds ratio of above 1.7 and probably exclude SNPs with an odds ratio above 1.2. This indicates that many, and even most, of the candidate gene association studies reported to date are likely to be falsepositive findings and that until sample sizes in ASD research reach those in other complex disorders such as schizophrenia, there is not sufficient power to reliably detect common variants of week effect contributing to ASD risk. Dr. Buxbaum finished the session with an overview of the methods of high-throughput (“next-generation”) sequencing and summarized the ongoing large-scale whole-exome sequencing being carried out in ASDs. Dr. Buxbaum, together with Dr. Devlin and others, is part of a multi-site study to complete whole-exome sequencing in 1000 ASD cases and 1000 matched controls as a means to identify additional risk loci for ASD. Dr. Scherer heads a similar independent effort. Given the likelihood that a significant proportion of ASD is the results of rare variants of major effect (as discussed by Drs. Betancur and Scherer), these approaches hold great promise to bring us to the post-discovery era in ASD enomics.
Imaging in autism spectrum disorders Much has been said about the limiting amount of very high quality postmortem tissue available in ASDs. This deficit, which is being addressed by many of the advocacy groups including Autism Speaks, is in part balanced by the exceptional, careful structural and functional imaging studies going on. The careful reader will however have recognized that many imaging studies are being carried out on higher functioning subjects, although several sites, including the M. I.N.D. Institute/UC Davis and UC San Diego, have developed protocols suitable for more representative groups of subjects.
2
B RA IN RE S EAR CH 1 38 0 (2 0 1 1) 1 – 2
A recurrent theme during the meeting was the notion of early brain overgrowth in subject with autism, which has been documented in many ways, from simple biometric measurement of head circumference, brain structural imaging, as well as neuropathologically using quantitative tools (Dr. Eric Couchesne, UCSD). Several speakers discussed the need to understand in detail the deficits in cortical connectivity that reflect the existence of areas of abnormal cortical activation or cortical specialization. Recent studies involving structural studies of grey and white matter integrity in autism, as well as functional imaging of cortical networks, have demonstrated a certain degree of underconnectivity in distributed network in ASDs as well as deficit in the default mode network during resting state (Dr. Kimberly Stigler, Indiana University). Using self-organizing maps to calculate connectivity, Dr. Catherine Lord (University of Michigan) showed that adolescent with ASDs have a weaker connectivity between the posterior hub of the default network and the superior frontal cortex compared to controls. Such functional alterations are in turn fully compatible with an emerging number of rigorous neuropathological analyses that demonstrate abnormal numbers of neurons in discrete brain territories, such as the lateral amygdala (Drs. Cyndi Schumann and David Amaral, UC Davis), or in the fusiform face area and frontoinsular cortex (Dr. Hof). These converging data point to the need to develop novel methodologies to assess such discrete functional and anatomical changes across the entire lifespan as some manifestations of ASDs are likely to vary considerably during development. In this context, Dr. Karen Pierce (UCSD) eloquently presented new data obtained in very young children using sleep fMRI, and discussed the potential of this approach for early diagnosis and biomarker discovery. The relatively circumscribed – and variable – neuropathological changes seen in ASD patients will require a deeper analysis at the single cell level. While much can be done in animal models, a molecular analysis of postmortem neuro-
pathological materials remains crucial. Dr. Gene Blatt, from Boston University, presented evidence for disruption of inhibitory neurotransmission in the fusiform gyrus and posterior cingulate cortex, using ligand-binding autoradiography, revealing imbalances in GABA and benzodiazepine receptors numbers and affinity in ASD, which could be directly related to the behavioral and social core disturbances that characterize patients with ASDs.
Conclusions Altogether the symposium was distinguished by a series of excellent presentations and we are very grateful to the speakers who were willing to give of their time to present new and exciting data. We are also very grateful to the participants, both for their engaging questions and for the 100 posters that were presented at the meeting. In addition, we appreciate the anonymous reviewers and, in particular, we appreciate the unstinting help of Dr. Catalina Betancur who took the lead on organizing the review of all abstracts. Finally, we appreciate the ongoing input from all the members of the Organizing Committee (Drs. Bloom, Sharp, Amaral, and Courchesne), and Dr. Paul Carton and the staff of Elsevier and Brain Research. This symposium was a year in the making, and thanks to all of these people and to all of the speakers, it was, in our opinion, a great success.
Joseph D. Buxbaum Patrick R. Hof Mount Sinai School of Medicine, New York, NY, USA 0006-8993/$ – see front matter © 2011 Published by Elsevier B.V. doi:10.1016/j.brainres.2011.02.030