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Behavioral analyses of animal models of intellectual and developmental disabilities
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Editorial
Behavioral analyses of animal models of intellectual and developmental disabilities ABSTRACT
Intellectual and developmental disabilities (IDDs) are a common group of disorders that frequently share overlapping symptoms, including cognitive deficits, altered attention, seizures, impaired social interactions, and anxiety. The causes of these disorders are varied ranging from early prenatal/postnatal insults to genetic variants that either cause or are associated with an increased likelihood of an IDD. As many of the symptoms observed in individuals with IDDs are a manifestation of altered nervous system function resulting in altered behaviors, it should not be surprising that the field is very dependent upon in vivo model systems. This special issue of Neurobiology of Learning and Memory is focused on the methods and approaches that are being used to model and understand these disorders in mammals. While surveys by the Pew Foundation continue to find a high degree of confidence/trust in scientists by the public, several recent studies have documented issues with reproducibility in scientific publications. This special issue includes both primary research articles and review articles in which careful attention has been made to transparently report methods and use rigorous approaches to ensure reproducibility. Although there have been and will continue to be remarkable advances for treatment of subset of IDDs, it is clear that this field is still in its early stages. There is no doubt that the strategies being used to model IDDs will continue to evolve. We hope this special issue will support this evolution so that we can maintain the trust of the public and elected officials, and continue developing evidence-based approaches to new therapeutics.
1. Introduction According to the Centers for Disease Control and Prevention, just under 14% of children in the United States have an intellectual and/or developmental disability (IDD) that can range from mild to severe (Boyle et al., 2011). Both environmental and genetic factors contribute to the pathophysiology of these disorders, and there is evidence that either the incidence of these disorders in increasing or they are being detected with higher frequency. While the causes of IDD are varied and the specific clinical symptoms are highly heterogeneous, individuals with IDDs frequently present with overlapping symptoms, including reduced cognitive abilities, altered attention, seizures, impaired social interactions, altered sensorymotor processing, and anxiety. In the early 1960s, President John F. Kennedy worked with an advisory panel to address the need to identify the etiology of intellectual disability so that new therapies could be developed (Walkley et al., 2019). The US government ultimately established the National Institutes of Child Health and Human Development (NICHD), now named the Eunice Kennedy Shriver NICHD, in honor of John Kennedy’s sister who took up the mantle of advocating for individuals with IDDs. The NICHD, in turn, funded a number of Intellectual and Developmental Disabilities Research Centers (IDDRCs) at various academic institutions in the United States (for discussion, see Walkley et al., 2019). These centers support core services that are intended to accelerate the discovery of causes, and to develop new treatments, for these disorders. In addition, these centers provide a collaborative intellectual home for IDD researchers at their individual institutions. Annual meetings of the Directors of the IDDRCs have been a longstanding tradition. Recently, several factors led to a change in the format of these meetings, placing more emphasis on scientific advances that are causing the field to evolve, exploring opportunities for collaborations between the centers and with the broader community of https://doi.org/10.1016/j.nlm.2019.107087
1074-7427/ © 2019 Elsevier Inc. All rights reserved.
researchers in the field, and bringing together experts who provide specific services at the various IDDRCs so that they can share best practices. Given the impact of these disorders on behavior, it should not be surprising that essentially all of the IDDRCs support behavioral testing facilities for mammalian models of IDD. The leaders of these facilities presented descriptions of their core services at the 2016 IDDRC Directors meeting in Philadelphia. Based on the high level of interest expressed by attendees, participant and journal Editor, Dr. Ted Abel suggested that this group might organize a special issue of Neurobiology of Learning and Memory. 2. This special issue Over the last decade, several studies have raised concerns about the reproducibility of scientific observations and the potential impact on translation of interventions from preclinical/animal models to humans (Begley & Ioannidis, 2015; Begley, Buchan, & Dirnagl, 2015; Bespalov, Barnett, & Begley, 2018; Collins & Tabak, 2014; Jarvis & Williams, 2016; Landis et al., 2012; Prinz, Schlange, & Asadullah, 2011). Part of the problem originates from the fact that pharmacokinetics (absorption, distribution, and metabolism) are highly variable across species. In addition, structural challenges inherent in clinical trials, and unavoidable differences between rodent and human behaviors, are likely to explain translational discrepancies. However, there are concerns with the reproducibility of data in peer-reviewed, published scientific articles. This special issue starts with a review article by Maria Gulinello and co-authors from seven of the IDDRCs (Gulinello et al., 2018). This group first shares their general experience with strategies used to ensure reproducibility with behavioral analyses. They then offer an in-depth discussion of the novel object recognition task, a commonly deployed measure of cognitive function. The task takes advantage of the tendency
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of rodents to prefer exploration of a novel object as compared to an object with which they had prior exposure. Different effective protocols are described, including photographs of matched pairs of novel objects that worked well in various labs, and several appropriate statistical analyses. The authors systematically describe several potential sources of variability and potential outcomes depending on how the measures are performed. While some of the advice is specific to this particular task, the authors include descriptions of many factors that could influence results of a range of behavioral assays. This is followed by a review by Amy Ryan and colleagues who discuss the use of rat (Rattus norvegicus) and rhesus macaque (Macaca mulatta) to model neurodevelopmental disabilities (Ryan, Berman, & Bauman, 2018). In particular, they describe the unique features of these species that make them particularly amenable to model a number of behaviors observed in individuals with IDDs, including anxiety, repetitive behaviors/restricted interest, social development, and cognitive development. They review behavioral analyses of both a genetic (Fmr1) and environmental (prenatal maternal immune activation) rat model of neurodevelopmental disorders. They also discuss examples of the ways in which the rhesus macaque has been uniquely used to model neurodevelopmental disabilities (both genetic approaches and maternal-fetal immune interactions), to explore novel treatments, and to test for potential linkages of the vaccine additive, thimerosal, to altered social behavior. One concern frequently raised with behavioral analyses is the effect of inter-rater variability. Kenneth McCarson and colleagues describe the utility of force-plate actimeter-based systems to monitor motor activity (McCarson, Winter, Abrahamson, Berman, & Smith, 2018). They use this technology to study four examples of behaviors that are particularly well-suited for analyses with this technology, including pain sensitivity, hyperlocomotion/circling, photophobia, and repetitive movements. This last set of analyses is performed in a mouse that harbors mutations in two genes that are linked to Tourette Syndrome. Some brain structures have been strongly linked to certain behavioral domains that make them logical targets of investigation within the context of intellectual and developmental disabilities. In this special issue, Yue Li and colleagues summarize the evidence that links learning and memory to hippocampal function (Li, Shen, Stockton, & Zhao, 2018). They review the hippocampal deficits that are observed in humans with several different neurodevelopmental disabilities, including autism, Fragile X, Rett Syndrome, Trisomy 21 (Down syndrome), 15q chromosomal abnormalities, and fetal alcohol spectrum disorders. They also describe the hippocampal alterations that have been observed in mouse models of these disorders where dysfunction in cellular and molecular pathways can be correlated with altered behaviors and manipulated to define the conditions under which dysfunction can be corrected. In an analogous fashion, Aaron Sathyanesan and Vittorio Gallo review the role of cerebellum in locomotor activity and locomotor learning within the context of the developing nervous system (Sathyanesan & Gallo, 2018). They also review the advantages and disadvantages of the Erasmus Ladder, an automated system that uses a horizontal ladder and pressure sensors to measure stepping patterns in mice. The protocol includes both a motor learning component and automated obstacles that allow analyses of adaptive behaviors. Complex behaviors are dependent on specific circuits and abnormal behaviors will likely be related to dysfunction at the circuit level. A variety of recent advances have made it possible to both monitor and manipulate activity of select cells in specific circuits. Dong-oh Seo and colleagues review recent developments with optogenetic (optically activated) and chemogenetic (ligand activated) tools that have been developed to modulate the membrane potential of cells or signaling cascades within cells (Seo, Motard, & Bruchas, 2018), providing a
mechanism to use exogenous signals (light or chemical) to modulate the activity of cells in the nervous system. They discuss the advantages and the disadvantages of the current viral vector systems that are employed to express the genetic tools in subpopulations of cells. They also review how these tools have been deployed to study circuits that underlie several different neurodevelopmental disabilities, including autism, schizophrenia, obsessive compulsive disorder, and attention-deficit hyperactivity disorder. They finish with a sobering discussion of the complexity of using this type of approach to understand and ultimately treat humans with these conditions. This is followed by an article from Meera Modi and Mustafa Sahin who describe strategies to integrate data from several different measures of neuronal signaling, including measures of neurotransmitter release with amperometry, calcium levels with genetic sensors (used as a surrogate measure of neuronal activity), multi-electrode recording, local field potentials and electroencephalography (EEG) (Modi & Sahin, 2018). They review how these approaches have been used to develop an understanding of the various components of circuits that underlie social processing and how gene variants associated with disrupted social behavior affect different aspects of the circuits that control social behaviors. They close with a discussion of how circuit-based manipulations might lead to new therapeutics. Specific circuits underlying the development of complex behaviors can be disrupted by environmental causes. Susan Maloney and colleagues review evidence that certain anesthetic and sedative agents can cause apoptotic neuronal loss and long-term functional deficits (Maloney et al., 2018). They provide a balanced discussion of the evidence supporting such a linkage and of the evidence that does not support this linkage. In balance, they conclude that it seems unlikely that a single exposure causes an increase in risk, but that multiple exposures may increase the risk of an adverse neurobehavioral outcome. They describe a detailed protocol for a proposed method to critically evaluate the effects of anesthetic agents on the developing nervous system, including neuropathology, electrophysiology, and behavioral analyses, and further suggest the addition of in vivo neuroimaging techniques (MRI and functional connectivity) to provide a better understanding of the neural elements involved. Several studies have linked maternal infection and inflammation with neurodevelopmental disabilities. In this special issue, Zhi Zhang and colleagues describe the effects of intrauterine lipopolysaccharide (LPS), an endotoxin that triggers microglial activation, on cerebellar development in white rabbits (Zhang et al., 2018). They show microglial activation, increased levels of mRNA for several pro- and antiinflammatory cytokines, cerebellar neuropathology, and decreased cerebellar-dependent learning and memory. Qiumin Tan and Huda Zoghbi use several examples of genes (MECP2, SHANK3, CIC, and PUM1) that have been linked to human diseases to describe the effects of gene dosage (haploinsufficiency/duplication) on disease phenotype (Tan & Zoghbi, 2018). They document examples in which studies of the effects of gene dosage in mice led to identification of new human diseases. Finally, they provide a roadmap for investigators who are thinking of following up on gene variants of unknown significance. Christopher Angelakos and colleagues measure activity in four different, monogenic mouse models of autism spectrum disorder, including Shank3b−/−, Cntnap2−/−, Pcdh10+/−, and Frm1 knockout mice (Angelakos, Tudor, Ferri, Jongens, & Abel, 2019). In all but the Frm1 knockout mice, both sexes were examined. Locomotor activity was lower in males of all four genetic models, particularly during the dark (active) phase. In two of the models, the differences in activity were sex specific, with no differences observed in females. They also discuss potential reasons for why this decreased activity had not been observed in earlier studies.
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Mallory Kerner-Rossi and colleagues review the neuropathogenesis of Christianson syndrome and describe sensory deficits and associated neuropathology in a mouse model of this disorder (Kerner-Rossi, Gulinello, Walkley, & Dobrenis, 2018). Christianson syndrome is caused by loss-of-function mutations in Na+/H+ exchanger, also known as NHE6 or Slc9a6, a transporter important for the regulation of endosomal pH. They show sensory deficits including reduced responses to noxious thermal and mechanical stimuli, that are associated with accumulation of glycosphingolipid in spinal cord and microglial activation. They also discuss evidence of altered sensory processing in autism. Solmi Cheon and colleagues review the evidence linking disorders in the ubiquitin proteasome pathway to neurodevelopmental and psychiatric disorders (Cheon, Dean, & Chahrour, 2018). This pathway engages two relatively small families of ligases (E1 and E2) that transfer ubiquitin to a family of between 600 and 700 E3 ligases. These ultimately transfer ubiquitin to presumably specific subsets of proteins and target these proteins for either proteosomal degradation or de-ubiquitination (for review, see George, Hoffiz, Charles, Zhu, & Mabb, 2018). Several different mutations in genes in this pathway have been linked to autism, intellectual disability, attention-deficit hyperactivity disorder (ADHD), and schizophrenia. They close with a description of several drugs that target this pathway and have already been approved by the FDA. They discuss pros and cons of using these drugs to treat some neurodevelopmental disabilities. Anna Adhirari and colleagues describe cognitive impairments in a mouse model of Prader-Willi syndrome (Adhikari et al., 2018). They tested mice with heterozygous deletion of Snord116, a gene implicated in the pathogenesis of Prader-Willi, and show impairments in several tasks, including novel object recognition, location memory, and cued fear conditioning. They also present analyses of several motor tasks that were not altered in this mouse model. This special issue concludes with three articles that address difference aspects of Rett syndrome, an X-linked neurodevelopmental disorder associated with seemingly normal development for the first 12 to 18 months of life followed by progressive loss of motor abilities, developmental milestones, intellectual disability, stereotypies and autonomic dysfunction. Rett syndrome is caused by loss-of-function mutations in the gene that encodes for methyl-CpG binding protein 2, a protein that recognizes methylated cytosine-guanosine enriched sequences and is required for translating this epigenetic modification of DNA into altered transcription. Although many of the disease-associated mutations in MECP2 are found in the domain that is required for binding methylated CpG islands, disease-associated mutations are found in several other regions of the protein. The function of some of these other regions are still being elucidated. Methyl-CpG binding protein 2 is widely distributed in the nervous system, but it is not known if disease requires loss-of-function in all cells or just in subsets of cells. This section starts with an article by Elizabeth Smith and colleagues who review what is known about the correlations between the structural alterations and behavioral deficits in loss of function mouse models of Mecp2 deficiency (Smith et al., 2018). They also add a new dimension by testing for differences in brain structure and behavior at different ages with some differences only observed at early stages and others only observed at later stages of development. This analysis highlights the complexity of developing a mechanistic understanding of disease pathogenesis when it occurs within the context of a developing (dynamic) nervous system. The level of phosphorylated methyl-CpG binding protein is increased in response to neuronal activation. While several studies have focused on generating models in which the phosphorylation sites (serine residues in this case) are mutated to an alanine, relatively few studies have focused on studies of models in which the serine residues are mutated to a residue that is thought to mimic the structure of
phosphorylated serine (e.g. glutamate). In fact, there are two phosphorylation sites on methyl-CpG binding protein. Xiofen Zhong and colleagues generated a new phosphomimetic mutant mouse line, S421E, and examined the effects of this mutation on synapse density, synaptic scaling, and contextual fear memory (Zhong, Li, Kim, & Chang, 2018). They also review the results of several studies of the role of the two different serine residues and conclude that the role of the two residues are opposite. This provides an interesting alternative approach to modulation of the activity of methyl-CpG binding protein. Finally, we conclude with a review article by Hua Yang and colleagues (Yang, Li, Han, Zhou, & Zhou, 2018). They describe the results that have been obtained with various mouse models of Rett syndrome that harbor many of the mutations that have been identified in patients. In many cases, these mutations have revealed important insights into the mechanisms by which methyl-CpG binding protein 2 regulates gene expression. They also review evidence that selective deletion of Mecp2 in brain is sufficient to mimic the disorder, arguing that loss-of-function from peripheral tissues is not required for the most salient of the symptoms. Finally, they review evidence that post-natal correction may be sufficient to reverse many of the symptoms of the disease. 3. Conclusion The causes of neurodevelopmental disabilities are diverse, including both environmental and genetic factors. The environmental factors linked to neurodevelopmental disabilities suggest risk factors arising from older paternal age, early prenatal/neonatal infection, prematurity, trauma, toxin exposures, etc. (Chen, Giri, Xia, Subedi, & Li, 2017; Emerson & Hatton, 2007; Emerson, 2007; Farah, 2017; Heuvelman et al., 2018; Rosen, Lee, Lee, Yang, & Burstyn, 2015; Xie et al., 2017). The elucidation of the sequence of the human genome led to an explosion of our understanding of the genetic contributions to intellectual and developmental disabilities (Chiurazzi & Pirozzi, 2016). To date, several hundred genes and many more gene variants have been linked to various neurodevelopmental disabilities (Cardoso et al., 2019; Grove et al., 2019; Oyrer et al., 2018; Tarlungeanu & Novarino, 2018; Waye & Cheng, 2018). While there are many examples of gene variants of unknown significance and gene variants that do not invariably cause disease (not highly penetrant), in many cases the mutations have been clearly demonstrated to cause (or at least contribute to) the pathogenesis of IDDs. In addition to the gene variants that are likely to have a relatively direct impact on brain function (e.g. synaptic proteins, neurotransmitter receptors/transporters, etc), mutations in several genes that control general cellular functions (e.g. RNA translation, epigenetics, protein trafficking through subcellular compartments, and protein degradation), that are not likely to be specific to brain function, also have been linked to IDDs. The identification of these specific gene variants as strong risk factors for neurodevelopmental disabilities has and will continue to have a dramatic impact on our understanding of these complex biologic processes. In many cases, mutations in the same gene cause different pathologies. This occurs for a variety reasons. Some mutations have gain-of-function properties and others cause a loss-of-function. Many proteins have multiple functions that are mediated by distinct domains. Background genes may increase risk or confer protection. Further, in addition to germline mutations, we now know that somatic mutations, localized to a subset of brain regions and/or peripheral organs, are not infrequent (D'Gama et al., 2015; D'Gama et al., 2017; Lodato et al., 2015; Poduri, Evrony, Cai, & Walsh, 2013). While this wealth of potential causes may seem daunting, the field has made remarkable progress. We need to make sure that we educate both parent groups and legislators. Stakeholders are appropriately impatient with the pace of translation, but it seems clear that many agree
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that mechanistic understanding of the pathogenesis of these disorders will eventually improve the outcomes for this group of disorders. Ultimately, these groups also need to trust the science that we produce. We all recognize that science evolves and that this will impact the interpretation of our results. One hopes that our data are at least reproducible, and that we can discuss the interpretation of the results with sufficient humility to avoid misleading the public. Although the myriad environmental and genetic causes of IDDs seem overwhelming in their complextiy, significant advances have been made in terms of understanding the relationship between these influences and functional outcomes like behavioral disturbances. It is our responsibility as IDDrelated research scientists to provide clarity to the public concerning the importance of discovering mechanisms and translating those findings into therapeutic strategies. A constructive approach includes taking steps to maximize the reproducibility of our results and to be conservative about the claims related to them. Moreover, we should appropriately describe how animal research, which employs highlycontrolled experimental designs, provides significant direction in pursuing translational treatment approaches for developmental disorders that cannot be derived by human studies alone.
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E., & Bruchas, M. R. (2018). Contemporary strategies for dissecting the neuronal basis of neurodevelopmental disorders. Neurobiology of Learning and Memory. Smith, E. S., Smith, D. R., Eyring, C., Braileanu, M., Smith-Connor, K. S., Ei Tan, Y., ... Blue, M. E. (2018). Altered trajectories of neurodevelopment and behavior in mouse models of Rett syndrome. Neurobiology of Learning and Memory. Tan, Q., & Zoghbi, H. Y. (2018). Mouse models as a tool for discovering new neurological diseases. Neurobiology of Learning and Memory. Tarlungeanu, D. C., & Novarino, G. (2018). Genomics in neurodevelopmental disorders: An avenue to personalized medicine. Experimental & Molecular Medicine, 50, 100. Walkley, S. U., Abbeduto, L., Batshaw, M. L., Bhattacharyya, A., Bookheimer, S. Y., Christian, B. T., ... Intellectual, & Developmental Disabilities Research Centers Directors, C. (2019). Intellectual and developmental disabilities research centers: Fifty years of scientific accomplishments. 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Acknowledgements The authors of this editorial were partially supported by their respective Intellectual and Developmental Disabilities Research Centers that are funded by the Eunice Kennedy Shriver National Institutes of Health, including, UC Davis (U54 HD079125), Boston Children’s Hospital (U54 HD090255), Vanderbilt University (U54 HD083211), Baylor College of Medicine (U54 HD083092), Washington University (U54 HD087011) and Children’s Hospital of Philadelphia/University of Pennsylvania (U54 HD0086984). The content of this editorial is solely the responsibility of the authors and does not necessarily represent the official view of the National Institute of Health. References Adhikari, A., Copping, N. A., Onaga, B., Pride, M. C., Coulson, R. L., Yang, M., ... Silverman, J. L. (2018). Cognitive deficits in the Snord116 deletion mouse model for Prader-Willi syndrome. Neurobiology of Learning and Memory. Angelakos, C. C., Tudor, J. C., Ferri, S. L., Jongens, T. A., & Abel, T. (2019). Home-cage hypoactivity in mouse genetic models of autism spectrum disorder. Neurobiology of Learning and Memory. Begley, C. G., Buchan, A. M., & Dirnagl, U. (2015). Robust research: Institutions must do their part for reproducibility. Nature, 525, 25–27. Begley, C. G., & Ioannidis, J. P. (2015). Reproducibility in science: Improving the standard for basic and preclinical research. Circulation Research, 116, 116–126. Bespalov, A., Barnett, A. G., & Begley, C. G. (2018). Industry is more alarmed about reproducibility than academia. Nature, 563, 626. Boyle, C. A., Boulet, S., Schieve, L. A., Cohen, R. A., Blumberg, S. J., Yeargin-Allsopp, M., ... Kogan, M. D. (2011). Trends in the prevalence of developmental disabilities in US children, 1997–2008. Pediatrics, 127, 1034–1042. Cardoso, A. R., Lopes-Marques, M., Silva, R. M., Serrano, C., Amorim, A., Prata, M. J., & Azevedo, L. (2019). Essential genetic findings in neurodevelopmental disorders. Hum Genomics, 13, 31. Chen, T., Giri, M., Xia, Z., Subedi, Y. N., & Li, Y. (2017). Genetic and epigenetic mechanisms of epilepsy: A review. Neuropsychiatric Disease and Treatment, 13, 1841–1859. Cheon, S., Dean, M., & Chahrour, M. (2018). The ubiquitin proteasome pathway in neuropsychiatric disorders. Neurobiology of Learning and Memory. Chiurazzi, P., & Pirozzi, F. (2016). Advances in understanding - genetic basis of intellectual disability. F1000Research, 5. Collins, F. S., & Tabak, L. A. (2014). Policy: NIH plans to enhance reproducibility. Nature, 505, 612–613. D'Gama, A. M., Pochareddy, S., Li, M., Jamuar, S. S., Reiff, R. E., Lam, A. N., ... Walsh, C. A. (2015). Targeted DNA sequencing from autism spectrum disorder brains implicates multiple genetic mechanisms. Neuron, 88, 910–917. D'Gama, A. M., Woodworth, M. B., Hossain, A. A., Bizzotto, S., Hatem, N. E., LaCoursiere, C. M., ... Walsh, C. A. (2017). Somatic mutations activating the mTOR pathway in dorsal telencephalic progenitors cause a continuum of cortical dysplasias. Cell Rep, 21, 3754–3766. Emerson, E. (2007). Poverty and people with intellectual disabilities. Mental Retardation and Developmental Disabilities Research Reviews, 13, 107–113.
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Jacqueline N. Crawleya MIND Institute, Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA 95821, USA a
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Michela Fagiolinib b Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02459, USA
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Fiona E. Harrison Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37323, USA
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David F. Wozniake Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA Michael B. Robinsonf, Departments of Pediatrics and Systems Pharmacology & Translational Therapeutics, Children’s Hospital of Philadelphia/University of Pennsylvania, Philadelphia, PA 19104, USA E-mail address: [email protected]. ⁎
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Rodney Samacod Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Corresponding author. 5
Contents lists available at ScienceDirect
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Editorial
Behavioral analyses of animal models of intellectual and developmental disabilities ABSTRACT
Intellectual and developmental disabilities (IDDs) are a common group of disorders that frequently share overlapping symptoms, including cognitive deficits, altered attention, seizures, impaired social interactions, and anxiety. The causes of these disorders are varied ranging from early prenatal/postnatal insults to genetic variants that either cause or are associated with an increased likelihood of an IDD. As many of the symptoms observed in individuals with IDDs are a manifestation of altered nervous system function resulting in altered behaviors, it should not be surprising that the field is very dependent upon in vivo model systems. This special issue of Neurobiology of Learning and Memory is focused on the methods and approaches that are being used to model and understand these disorders in mammals. While surveys by the Pew Foundation continue to find a high degree of confidence/trust in scientists by the public, several recent studies have documented issues with reproducibility in scientific publications. This special issue includes both primary research articles and review articles in which careful attention has been made to transparently report methods and use rigorous approaches to ensure reproducibility. Although there have been and will continue to be remarkable advances for treatment of subset of IDDs, it is clear that this field is still in its early stages. There is no doubt that the strategies being used to model IDDs will continue to evolve. We hope this special issue will support this evolution so that we can maintain the trust of the public and elected officials, and continue developing evidence-based approaches to new therapeutics.
1. Introduction According to the Centers for Disease Control and Prevention, just under 14% of children in the United States have an intellectual and/or developmental disability (IDD) that can range from mild to severe (Boyle et al., 2011). Both environmental and genetic factors contribute to the pathophysiology of these disorders, and there is evidence that either the incidence of these disorders in increasing or they are being detected with higher frequency. While the causes of IDD are varied and the specific clinical symptoms are highly heterogeneous, individuals with IDDs frequently present with overlapping symptoms, including reduced cognitive abilities, altered attention, seizures, impaired social interactions, altered sensorymotor processing, and anxiety. In the early 1960s, President John F. Kennedy worked with an advisory panel to address the need to identify the etiology of intellectual disability so that new therapies could be developed (Walkley et al., 2019). The US government ultimately established the National Institutes of Child Health and Human Development (NICHD), now named the Eunice Kennedy Shriver NICHD, in honor of John Kennedy’s sister who took up the mantle of advocating for individuals with IDDs. The NICHD, in turn, funded a number of Intellectual and Developmental Disabilities Research Centers (IDDRCs) at various academic institutions in the United States (for discussion, see Walkley et al., 2019). These centers support core services that are intended to accelerate the discovery of causes, and to develop new treatments, for these disorders. In addition, these centers provide a collaborative intellectual home for IDD researchers at their individual institutions. Annual meetings of the Directors of the IDDRCs have been a longstanding tradition. Recently, several factors led to a change in the format of these meetings, placing more emphasis on scientific advances that are causing the field to evolve, exploring opportunities for collaborations between the centers and with the broader community of https://doi.org/10.1016/j.nlm.2019.107087
1074-7427/ © 2019 Elsevier Inc. All rights reserved.
researchers in the field, and bringing together experts who provide specific services at the various IDDRCs so that they can share best practices. Given the impact of these disorders on behavior, it should not be surprising that essentially all of the IDDRCs support behavioral testing facilities for mammalian models of IDD. The leaders of these facilities presented descriptions of their core services at the 2016 IDDRC Directors meeting in Philadelphia. Based on the high level of interest expressed by attendees, participant and journal Editor, Dr. Ted Abel suggested that this group might organize a special issue of Neurobiology of Learning and Memory. 2. This special issue Over the last decade, several studies have raised concerns about the reproducibility of scientific observations and the potential impact on translation of interventions from preclinical/animal models to humans (Begley & Ioannidis, 2015; Begley, Buchan, & Dirnagl, 2015; Bespalov, Barnett, & Begley, 2018; Collins & Tabak, 2014; Jarvis & Williams, 2016; Landis et al., 2012; Prinz, Schlange, & Asadullah, 2011). Part of the problem originates from the fact that pharmacokinetics (absorption, distribution, and metabolism) are highly variable across species. In addition, structural challenges inherent in clinical trials, and unavoidable differences between rodent and human behaviors, are likely to explain translational discrepancies. However, there are concerns with the reproducibility of data in peer-reviewed, published scientific articles. This special issue starts with a review article by Maria Gulinello and co-authors from seven of the IDDRCs (Gulinello et al., 2018). This group first shares their general experience with strategies used to ensure reproducibility with behavioral analyses. They then offer an in-depth discussion of the novel object recognition task, a commonly deployed measure of cognitive function. The task takes advantage of the tendency
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of rodents to prefer exploration of a novel object as compared to an object with which they had prior exposure. Different effective protocols are described, including photographs of matched pairs of novel objects that worked well in various labs, and several appropriate statistical analyses. The authors systematically describe several potential sources of variability and potential outcomes depending on how the measures are performed. While some of the advice is specific to this particular task, the authors include descriptions of many factors that could influence results of a range of behavioral assays. This is followed by a review by Amy Ryan and colleagues who discuss the use of rat (Rattus norvegicus) and rhesus macaque (Macaca mulatta) to model neurodevelopmental disabilities (Ryan, Berman, & Bauman, 2018). In particular, they describe the unique features of these species that make them particularly amenable to model a number of behaviors observed in individuals with IDDs, including anxiety, repetitive behaviors/restricted interest, social development, and cognitive development. They review behavioral analyses of both a genetic (Fmr1) and environmental (prenatal maternal immune activation) rat model of neurodevelopmental disorders. They also discuss examples of the ways in which the rhesus macaque has been uniquely used to model neurodevelopmental disabilities (both genetic approaches and maternal-fetal immune interactions), to explore novel treatments, and to test for potential linkages of the vaccine additive, thimerosal, to altered social behavior. One concern frequently raised with behavioral analyses is the effect of inter-rater variability. Kenneth McCarson and colleagues describe the utility of force-plate actimeter-based systems to monitor motor activity (McCarson, Winter, Abrahamson, Berman, & Smith, 2018). They use this technology to study four examples of behaviors that are particularly well-suited for analyses with this technology, including pain sensitivity, hyperlocomotion/circling, photophobia, and repetitive movements. This last set of analyses is performed in a mouse that harbors mutations in two genes that are linked to Tourette Syndrome. Some brain structures have been strongly linked to certain behavioral domains that make them logical targets of investigation within the context of intellectual and developmental disabilities. In this special issue, Yue Li and colleagues summarize the evidence that links learning and memory to hippocampal function (Li, Shen, Stockton, & Zhao, 2018). They review the hippocampal deficits that are observed in humans with several different neurodevelopmental disabilities, including autism, Fragile X, Rett Syndrome, Trisomy 21 (Down syndrome), 15q chromosomal abnormalities, and fetal alcohol spectrum disorders. They also describe the hippocampal alterations that have been observed in mouse models of these disorders where dysfunction in cellular and molecular pathways can be correlated with altered behaviors and manipulated to define the conditions under which dysfunction can be corrected. In an analogous fashion, Aaron Sathyanesan and Vittorio Gallo review the role of cerebellum in locomotor activity and locomotor learning within the context of the developing nervous system (Sathyanesan & Gallo, 2018). They also review the advantages and disadvantages of the Erasmus Ladder, an automated system that uses a horizontal ladder and pressure sensors to measure stepping patterns in mice. The protocol includes both a motor learning component and automated obstacles that allow analyses of adaptive behaviors. Complex behaviors are dependent on specific circuits and abnormal behaviors will likely be related to dysfunction at the circuit level. A variety of recent advances have made it possible to both monitor and manipulate activity of select cells in specific circuits. Dong-oh Seo and colleagues review recent developments with optogenetic (optically activated) and chemogenetic (ligand activated) tools that have been developed to modulate the membrane potential of cells or signaling cascades within cells (Seo, Motard, & Bruchas, 2018), providing a
mechanism to use exogenous signals (light or chemical) to modulate the activity of cells in the nervous system. They discuss the advantages and the disadvantages of the current viral vector systems that are employed to express the genetic tools in subpopulations of cells. They also review how these tools have been deployed to study circuits that underlie several different neurodevelopmental disabilities, including autism, schizophrenia, obsessive compulsive disorder, and attention-deficit hyperactivity disorder. They finish with a sobering discussion of the complexity of using this type of approach to understand and ultimately treat humans with these conditions. This is followed by an article from Meera Modi and Mustafa Sahin who describe strategies to integrate data from several different measures of neuronal signaling, including measures of neurotransmitter release with amperometry, calcium levels with genetic sensors (used as a surrogate measure of neuronal activity), multi-electrode recording, local field potentials and electroencephalography (EEG) (Modi & Sahin, 2018). They review how these approaches have been used to develop an understanding of the various components of circuits that underlie social processing and how gene variants associated with disrupted social behavior affect different aspects of the circuits that control social behaviors. They close with a discussion of how circuit-based manipulations might lead to new therapeutics. Specific circuits underlying the development of complex behaviors can be disrupted by environmental causes. Susan Maloney and colleagues review evidence that certain anesthetic and sedative agents can cause apoptotic neuronal loss and long-term functional deficits (Maloney et al., 2018). They provide a balanced discussion of the evidence supporting such a linkage and of the evidence that does not support this linkage. In balance, they conclude that it seems unlikely that a single exposure causes an increase in risk, but that multiple exposures may increase the risk of an adverse neurobehavioral outcome. They describe a detailed protocol for a proposed method to critically evaluate the effects of anesthetic agents on the developing nervous system, including neuropathology, electrophysiology, and behavioral analyses, and further suggest the addition of in vivo neuroimaging techniques (MRI and functional connectivity) to provide a better understanding of the neural elements involved. Several studies have linked maternal infection and inflammation with neurodevelopmental disabilities. In this special issue, Zhi Zhang and colleagues describe the effects of intrauterine lipopolysaccharide (LPS), an endotoxin that triggers microglial activation, on cerebellar development in white rabbits (Zhang et al., 2018). They show microglial activation, increased levels of mRNA for several pro- and antiinflammatory cytokines, cerebellar neuropathology, and decreased cerebellar-dependent learning and memory. Qiumin Tan and Huda Zoghbi use several examples of genes (MECP2, SHANK3, CIC, and PUM1) that have been linked to human diseases to describe the effects of gene dosage (haploinsufficiency/duplication) on disease phenotype (Tan & Zoghbi, 2018). They document examples in which studies of the effects of gene dosage in mice led to identification of new human diseases. Finally, they provide a roadmap for investigators who are thinking of following up on gene variants of unknown significance. Christopher Angelakos and colleagues measure activity in four different, monogenic mouse models of autism spectrum disorder, including Shank3b−/−, Cntnap2−/−, Pcdh10+/−, and Frm1 knockout mice (Angelakos, Tudor, Ferri, Jongens, & Abel, 2019). In all but the Frm1 knockout mice, both sexes were examined. Locomotor activity was lower in males of all four genetic models, particularly during the dark (active) phase. In two of the models, the differences in activity were sex specific, with no differences observed in females. They also discuss potential reasons for why this decreased activity had not been observed in earlier studies.
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Mallory Kerner-Rossi and colleagues review the neuropathogenesis of Christianson syndrome and describe sensory deficits and associated neuropathology in a mouse model of this disorder (Kerner-Rossi, Gulinello, Walkley, & Dobrenis, 2018). Christianson syndrome is caused by loss-of-function mutations in Na+/H+ exchanger, also known as NHE6 or Slc9a6, a transporter important for the regulation of endosomal pH. They show sensory deficits including reduced responses to noxious thermal and mechanical stimuli, that are associated with accumulation of glycosphingolipid in spinal cord and microglial activation. They also discuss evidence of altered sensory processing in autism. Solmi Cheon and colleagues review the evidence linking disorders in the ubiquitin proteasome pathway to neurodevelopmental and psychiatric disorders (Cheon, Dean, & Chahrour, 2018). This pathway engages two relatively small families of ligases (E1 and E2) that transfer ubiquitin to a family of between 600 and 700 E3 ligases. These ultimately transfer ubiquitin to presumably specific subsets of proteins and target these proteins for either proteosomal degradation or de-ubiquitination (for review, see George, Hoffiz, Charles, Zhu, & Mabb, 2018). Several different mutations in genes in this pathway have been linked to autism, intellectual disability, attention-deficit hyperactivity disorder (ADHD), and schizophrenia. They close with a description of several drugs that target this pathway and have already been approved by the FDA. They discuss pros and cons of using these drugs to treat some neurodevelopmental disabilities. Anna Adhirari and colleagues describe cognitive impairments in a mouse model of Prader-Willi syndrome (Adhikari et al., 2018). They tested mice with heterozygous deletion of Snord116, a gene implicated in the pathogenesis of Prader-Willi, and show impairments in several tasks, including novel object recognition, location memory, and cued fear conditioning. They also present analyses of several motor tasks that were not altered in this mouse model. This special issue concludes with three articles that address difference aspects of Rett syndrome, an X-linked neurodevelopmental disorder associated with seemingly normal development for the first 12 to 18 months of life followed by progressive loss of motor abilities, developmental milestones, intellectual disability, stereotypies and autonomic dysfunction. Rett syndrome is caused by loss-of-function mutations in the gene that encodes for methyl-CpG binding protein 2, a protein that recognizes methylated cytosine-guanosine enriched sequences and is required for translating this epigenetic modification of DNA into altered transcription. Although many of the disease-associated mutations in MECP2 are found in the domain that is required for binding methylated CpG islands, disease-associated mutations are found in several other regions of the protein. The function of some of these other regions are still being elucidated. Methyl-CpG binding protein 2 is widely distributed in the nervous system, but it is not known if disease requires loss-of-function in all cells or just in subsets of cells. This section starts with an article by Elizabeth Smith and colleagues who review what is known about the correlations between the structural alterations and behavioral deficits in loss of function mouse models of Mecp2 deficiency (Smith et al., 2018). They also add a new dimension by testing for differences in brain structure and behavior at different ages with some differences only observed at early stages and others only observed at later stages of development. This analysis highlights the complexity of developing a mechanistic understanding of disease pathogenesis when it occurs within the context of a developing (dynamic) nervous system. The level of phosphorylated methyl-CpG binding protein is increased in response to neuronal activation. While several studies have focused on generating models in which the phosphorylation sites (serine residues in this case) are mutated to an alanine, relatively few studies have focused on studies of models in which the serine residues are mutated to a residue that is thought to mimic the structure of
phosphorylated serine (e.g. glutamate). In fact, there are two phosphorylation sites on methyl-CpG binding protein. Xiofen Zhong and colleagues generated a new phosphomimetic mutant mouse line, S421E, and examined the effects of this mutation on synapse density, synaptic scaling, and contextual fear memory (Zhong, Li, Kim, & Chang, 2018). They also review the results of several studies of the role of the two different serine residues and conclude that the role of the two residues are opposite. This provides an interesting alternative approach to modulation of the activity of methyl-CpG binding protein. Finally, we conclude with a review article by Hua Yang and colleagues (Yang, Li, Han, Zhou, & Zhou, 2018). They describe the results that have been obtained with various mouse models of Rett syndrome that harbor many of the mutations that have been identified in patients. In many cases, these mutations have revealed important insights into the mechanisms by which methyl-CpG binding protein 2 regulates gene expression. They also review evidence that selective deletion of Mecp2 in brain is sufficient to mimic the disorder, arguing that loss-of-function from peripheral tissues is not required for the most salient of the symptoms. Finally, they review evidence that post-natal correction may be sufficient to reverse many of the symptoms of the disease. 3. Conclusion The causes of neurodevelopmental disabilities are diverse, including both environmental and genetic factors. The environmental factors linked to neurodevelopmental disabilities suggest risk factors arising from older paternal age, early prenatal/neonatal infection, prematurity, trauma, toxin exposures, etc. (Chen, Giri, Xia, Subedi, & Li, 2017; Emerson & Hatton, 2007; Emerson, 2007; Farah, 2017; Heuvelman et al., 2018; Rosen, Lee, Lee, Yang, & Burstyn, 2015; Xie et al., 2017). The elucidation of the sequence of the human genome led to an explosion of our understanding of the genetic contributions to intellectual and developmental disabilities (Chiurazzi & Pirozzi, 2016). To date, several hundred genes and many more gene variants have been linked to various neurodevelopmental disabilities (Cardoso et al., 2019; Grove et al., 2019; Oyrer et al., 2018; Tarlungeanu & Novarino, 2018; Waye & Cheng, 2018). While there are many examples of gene variants of unknown significance and gene variants that do not invariably cause disease (not highly penetrant), in many cases the mutations have been clearly demonstrated to cause (or at least contribute to) the pathogenesis of IDDs. In addition to the gene variants that are likely to have a relatively direct impact on brain function (e.g. synaptic proteins, neurotransmitter receptors/transporters, etc), mutations in several genes that control general cellular functions (e.g. RNA translation, epigenetics, protein trafficking through subcellular compartments, and protein degradation), that are not likely to be specific to brain function, also have been linked to IDDs. The identification of these specific gene variants as strong risk factors for neurodevelopmental disabilities has and will continue to have a dramatic impact on our understanding of these complex biologic processes. In many cases, mutations in the same gene cause different pathologies. This occurs for a variety reasons. Some mutations have gain-of-function properties and others cause a loss-of-function. Many proteins have multiple functions that are mediated by distinct domains. Background genes may increase risk or confer protection. Further, in addition to germline mutations, we now know that somatic mutations, localized to a subset of brain regions and/or peripheral organs, are not infrequent (D'Gama et al., 2015; D'Gama et al., 2017; Lodato et al., 2015; Poduri, Evrony, Cai, & Walsh, 2013). While this wealth of potential causes may seem daunting, the field has made remarkable progress. We need to make sure that we educate both parent groups and legislators. Stakeholders are appropriately impatient with the pace of translation, but it seems clear that many agree
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that mechanistic understanding of the pathogenesis of these disorders will eventually improve the outcomes for this group of disorders. Ultimately, these groups also need to trust the science that we produce. We all recognize that science evolves and that this will impact the interpretation of our results. One hopes that our data are at least reproducible, and that we can discuss the interpretation of the results with sufficient humility to avoid misleading the public. Although the myriad environmental and genetic causes of IDDs seem overwhelming in their complextiy, significant advances have been made in terms of understanding the relationship between these influences and functional outcomes like behavioral disturbances. It is our responsibility as IDDrelated research scientists to provide clarity to the public concerning the importance of discovering mechanisms and translating those findings into therapeutic strategies. A constructive approach includes taking steps to maximize the reproducibility of our results and to be conservative about the claims related to them. Moreover, we should appropriately describe how animal research, which employs highlycontrolled experimental designs, provides significant direction in pursuing translational treatment approaches for developmental disorders that cannot be derived by human studies alone.
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Acknowledgements The authors of this editorial were partially supported by their respective Intellectual and Developmental Disabilities Research Centers that are funded by the Eunice Kennedy Shriver National Institutes of Health, including, UC Davis (U54 HD079125), Boston Children’s Hospital (U54 HD090255), Vanderbilt University (U54 HD083211), Baylor College of Medicine (U54 HD083092), Washington University (U54 HD087011) and Children’s Hospital of Philadelphia/University of Pennsylvania (U54 HD0086984). The content of this editorial is solely the responsibility of the authors and does not necessarily represent the official view of the National Institute of Health. References Adhikari, A., Copping, N. A., Onaga, B., Pride, M. C., Coulson, R. L., Yang, M., ... Silverman, J. L. (2018). Cognitive deficits in the Snord116 deletion mouse model for Prader-Willi syndrome. Neurobiology of Learning and Memory. Angelakos, C. C., Tudor, J. C., Ferri, S. L., Jongens, T. A., & Abel, T. (2019). Home-cage hypoactivity in mouse genetic models of autism spectrum disorder. Neurobiology of Learning and Memory. Begley, C. G., Buchan, A. M., & Dirnagl, U. (2015). Robust research: Institutions must do their part for reproducibility. Nature, 525, 25–27. Begley, C. G., & Ioannidis, J. P. (2015). Reproducibility in science: Improving the standard for basic and preclinical research. Circulation Research, 116, 116–126. Bespalov, A., Barnett, A. G., & Begley, C. G. (2018). Industry is more alarmed about reproducibility than academia. Nature, 563, 626. Boyle, C. A., Boulet, S., Schieve, L. A., Cohen, R. A., Blumberg, S. J., Yeargin-Allsopp, M., ... Kogan, M. D. (2011). Trends in the prevalence of developmental disabilities in US children, 1997–2008. Pediatrics, 127, 1034–1042. Cardoso, A. R., Lopes-Marques, M., Silva, R. M., Serrano, C., Amorim, A., Prata, M. J., & Azevedo, L. (2019). Essential genetic findings in neurodevelopmental disorders. Hum Genomics, 13, 31. Chen, T., Giri, M., Xia, Z., Subedi, Y. N., & Li, Y. (2017). Genetic and epigenetic mechanisms of epilepsy: A review. Neuropsychiatric Disease and Treatment, 13, 1841–1859. Cheon, S., Dean, M., & Chahrour, M. (2018). The ubiquitin proteasome pathway in neuropsychiatric disorders. Neurobiology of Learning and Memory. Chiurazzi, P., & Pirozzi, F. (2016). Advances in understanding - genetic basis of intellectual disability. F1000Research, 5. Collins, F. S., & Tabak, L. A. (2014). Policy: NIH plans to enhance reproducibility. Nature, 505, 612–613. D'Gama, A. M., Pochareddy, S., Li, M., Jamuar, S. S., Reiff, R. E., Lam, A. N., ... Walsh, C. A. (2015). Targeted DNA sequencing from autism spectrum disorder brains implicates multiple genetic mechanisms. Neuron, 88, 910–917. D'Gama, A. M., Woodworth, M. B., Hossain, A. A., Bizzotto, S., Hatem, N. E., LaCoursiere, C. M., ... Walsh, C. A. (2017). Somatic mutations activating the mTOR pathway in dorsal telencephalic progenitors cause a continuum of cortical dysplasias. Cell Rep, 21, 3754–3766. Emerson, E. (2007). Poverty and people with intellectual disabilities. Mental Retardation and Developmental Disabilities Research Reviews, 13, 107–113.
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Jacqueline N. Crawleya MIND Institute, Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA 95821, USA a
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Michela Fagiolinib b Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02459, USA
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Fiona E. Harrison Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37323, USA
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David F. Wozniake Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA Michael B. Robinsonf, Departments of Pediatrics and Systems Pharmacology & Translational Therapeutics, Children’s Hospital of Philadelphia/University of Pennsylvania, Philadelphia, PA 19104, USA E-mail address: [email protected]. ⁎
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Rodney Samacod Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Corresponding author. 5