Beth Israel Deaconess Medical Center, Boston , MA
Principal Investigator: Matthew Anderson, MD, Ph.D.
Anderson Laboratory Translational Autism Research Program
This grant will be used to support the autism research performed by the Anderson Laboratory, which is focused on understanding the cellular and molecular mechanisms of autism and developing therapies aimed at treating it. Recent studies have uncovered copy number variations (CNV) in a subset of individuals with idiopathic, non-syndromic autism. Using mouse genetic engineering techniques and an array of biochemical, electrophysiological, and behavioral measurements, Dr. Anderson’s laboratory seeks to gain a deeper understanding of this still perplexing behavioral disorder. Using these novel tools and approaches, they seek answers to the following questions: 1) Do the CNVs cause behavioral deficits characteristic of autism (impaired social interaction and communication and increased repetitive behavior)? 2) What are the specific genes within these large deleted or duplicated genomic regions that cause the autism behavioral traits? 3) What specific neuronal populations and brain regions do these genetic defects cause the autism behavioral deficits? 4) What are the specific molecular and cellular defects within neuronal circuits that underlie these autism behavioral traits? 5) Do common pathophysiologic mechanisms exist across different etiologic causes of autism? 6) What behavioral and/or medical treatments can be targeted at these molecular and circuit defects to treat the autism?
Beth Israel Deaconess Medical Center
Boston University School of Medicine, Boston, MA
Principal Investigator: Tsuneya Ikezu, MD, PhD
Characterization of Microglial Wnt Signaling in Maternal Immune Activation-Related Autism
(co-funded with The Robert E. Landreth and Donna Landreth Family Fund)
There is a pressing need to develop novel therapies for autism spectrum disorders (ASD). Innate immune signaling is emerging as a key novel target, corroborated by mounting evidence implicating its involvement in ASD etiology. Maternal infection during pregnancy and subsequent innate immunity response may play a critical role in the development of ASD. Significantly elevated microglial activation has been shown in the cortical, subcortical and cerebellum regions in postmortem ASD brains, and by live PET imaging of young adult subjects with ASD. However, it remains unknown whether activated microglia are directly involved in neurodevelopmental abnormalities or clinical symptoms of ASD. Dr. Ikezu and colleagues have characterized the molecular interactome of microglia and neural stem cells, and found that Wingless-related MMTV integration site 5a (Wnt5a) is induced by microglial activation and critically induces dendrite arborization. Moreover, silencing of Wnt5a in microglia significantly diminished their effect on neural maturation.
Dr. Ikezu’s central hypothesis is that maternal immune activation (MIA) induces prenatal or perinatal microglial activation and excessive microglial production of neurotrophic factors including Wnt5a in offspring, leading to aberrant local synaptogenesis and axonal guidance during early brain development. His hypothesis has been formulated by exciting preliminary data that Wnt5a gene expression is significantly increased in microglia acutely isolated from MIA-treated embryos or neonates. Dr. Ikezu and colleagues will delineate whether microglia are responsible for particular synaptic abnormalities by assessing the effect of depleting microglia or microgliaspecific molecules in the MIA model of ASD. The results of this research will lead to an entirely novel paradigm for the role of microglia underlying pathobiology of MIA-induced ASD phenotype, and potentially other genetic models of ASD.
Brown University Institute for Brain Science, Providence, RI
Principal Investigator: Eric Morrow, MD, Ph.D.
Endosomal NHE6 in Long-Range Connectivity and Autism (Co-funded with the Simons Foundation)
Human mutations in NHE6 represent a novel autism-related developmental brain disorder. Such syndromic forms of autism have provided critical traction for discerning disease mechanisms and identifying potential treatment targets. Dr. Morrow’s group is also investigating an interesting and novel cellular mechanism, namely modulation of endosomal signaling through regulation of intra-endosomal proton concentration. They will link this mechanism to points of convergence for gene mechanism in autism, namely development of long-range circuitry, axonal branching and relevant signaling pathways. In addition, they will test a link between NHE6 and fever. Many parental reports have strongly suggested improvements in autism symptoms with fever, and neuronal pH has been pinpointed as one mediator of the effects of systemic fever on neuronal excitability. Dr. Morrow’s group will seek to reverse the cellular defects observed via addition of exogenous signaling molecules. Finally, they will attempt to develop a model for autistic regression in response to stress. If successful with these studies, they will create new opportunities to test treatments for circuit defects and/or to prevent regression in a subset of patients with autism. The research on this project is primarily led in Dr. Morrow’s lab. Dr. Morrow will be working in the setting of the Institute for Brain Science at Brown University. He will be collaborating closely with Dr. Julie Kauer, an electrophysiologist with over 20 years of experience in synaptic physiology and plasticity, and Dr. Pietro DeCamilli, a renowned neuronal cell biologist in the area of endocytosis. This pilot project will have broad impact in the field of autism because it will identify novel cellular mechanisms that are tightly linked to potential therapeutic strategies.
Eric Morrow, Brown University
Feinstein Institute, North Shore Hospital, Manhasset, NY
Principal Investigator: Betty Diamond, MD
Maternal Antibody as a Contributor to Autism Spectrum Disorder (co-funded with The Robert E. Landreth and Donna Landreth Family Fund)
There is growing evidence that the maternal immune response may affect development of the fetal brain and, in some instances, lead to Autism Spectrum Disorder (ASD). Dr. Diamond and colleagues have generated a panel of monoclonal anti-brain antibodies, cloned from B cells of women with brain-reactive serology and a child with ASD. They will explore the effects of these antibodies on fetal brain development in mice and subsequent brain function. They will employ histologic and behavioral assessments as well as imaging cerebral metabolism in behaving mice. Dr. Diamond and colleagues will translate their findings into a study of women with brain-reactive antibodies and a child with ASD to associate ASD-phenotype of the offspring with antigenic specificities of the mother. They will follow a cohort of pregnant women prospectively to learn how to identify an at risk pregnancies for eventual protection of such pregnancies with decoy antigen. They will also study the gene expression profile and function of microglial cells in our ASD models. It is believed that the microglia may be a particularly responsive therapeutic target.
Massachusetts Institute of Technology, Cambridge, MA
2013 – 2018
Ann Graybiel, Ph.D., MIT
Bernardo Sabatini, Ph.D., Harvard Medical School
Guoping Feng, Ph.D., MIT
Synaptic and Behavioral Functions of Striatal Projection Neurons in Autism and Autism Spectrum Disorders
The grant supports complementary activities in the laboratories of Professor Guoping Feng and Professor Ann M. Graybiel at MIT’s McGovern Institute for Brain Research and Professor Bernardo Sabatini at Harvard Medical School. It involves both a fellowship program and a research program.
The three-year fellowship program will enable the principal investigators to train and mentor one postdoctoral fellow in their respective laboratories to work on autism research. The primary goal of this postdoctoral training program is to provide postdoctoral fellows with intellectual challenges and a broad range of advanced research techniques that will shape their future as independent scientists and leaders in the field of autism research. The fellows will be given an opportunity to contribute to cutting edge research into understanding the neural mechanisms underlying autism spectrum disorders. During their fellowships, the postdoctoral fellows will have the opportunity to use genetic, biochemical, electrophysiological and behavioral approaches to dissect molecular, synaptic, and circuitry mechanisms of ASDs using animal models.
Professors Feng and Graybiel will embark on a concentrated research effort aimed at understanding how the synaptic and behavioral functions of the striatum are critical to autism and autism spectrum disorders (ASD). The focus of their research will be the medium spiny neurons of the striatum (known in the field as MSNs), because these neurons and the circuits in which they are embedded are now suspected to be key brain components affected in autism and ASD. Professor Bernardo Sabatini’s laboratory will focus on developmental and dynamical control of striatal circuitry by dopaminergic inputs.
Bernardo Sabatini Lab
Tufts University, Medford, MA
Principal Investigator: Theoharis Theoharides, MD, Ph.D., Sackler School for Graduate Biomedical Sciences, Tufts University
Predoctoral Fellowship – Theoharides Laboratory, Tufts University
This grant provides support for a predoctoral fellowship for a student in Theoharis Theoharides’ lab at Tufts University. Despite the rise in Autism Spectrum Disorders (ASD), characterized by social and stereotypic disabilities, there remains a lack of knowledge regarding disease causes or treatment. Mounting evidence supports the involvement of brain inflammation due to genetic, neurohormonal and environmental factors, as well as the role of immune dysfunction. The affected brain regions are rich in mast cells and microglia, the critical immune cells, which regulate neuronal function in the developing ASD brain. The kinase mammalian target of rapamycin (mTOR), which regulates immune cell proliferation and proinflammatory mediator expression, and the downstream cytoskeletal regulator of secretion, moesin, have recently been linked to ASD. High risk of some ASD subtypes is associated with gene mutations, which increase mTOR signaling and lower the brain moesin levels.
Dr. Theoharides’ laboratory cloned moesin protein and showed that a phosphorylation pattern was linked to inhibition of mast cells. They also reported increased serum levels of neurotensin (NT) in some ASD children, a peptide secreted from neurons and present in the gut and brain. They showed that corticotropin-releasing hormone (CRH) secreted under stress can stimulate human mast cells through a synergistic action with NT leading to proinflammatory mediator release.
Their hypothesis is that hyperactive mTOR and lack of regulation by moesin in mast cells and microglia is the missing link for gene-environmental factor interactions and brain inflammation in some ASD. Their studies will determine if mTOR and moesin regulate mast cell and microglial activation in response to NT and CRH. Their in vivo studies will determine the presence of brain inflammation in normal and moesin-deficient mice treated with NT and CRH, and the ASD-relevant concentrations of these triggers. Results will be essential to develop a unique ASD-like mouse model for behavioral studies, to identify molecular targets for inhibition of irregular immune cell responses and for effective ASD treatments.