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Program Highlights SOCIAL NEUROSCIENCE LABORATORY: TOWARD A BETTER UNDERSTANDING OF AUTISM AND SCHIZOPHRENIA SPECTRUM DISORDERS hat is it about our brains that “hardwires” us themselves and their families. While there are treat- Wto seek out interactions with other people and ments for some of the associated symptoms of ASD, to take pleasure in forming social relationships and there are not yet treatments that adequately help attachments, beginning in earliest infancy, and con- with the core social behavior symptoms. I felt moti- tinuing throughout life? vated to better understand the biology of ASD so that we could better help these patients.” These are qualities that seem so much a part of us that many of us take them for granted. But what Dr. Brodkin also recognized that he could fashion a happens during brain development that interferes career in medicine combining basic neuroscience with the development of sociability in individuals research with clinical care. “During medical school, with autism or schizophrenia spectrum disorders? I was lucky enough to meet and interact with peo- These are the questions ple like Steve Hyman, that drive work in the lab- Eric Nestler, and Eric oratory of Edward S. Kandel, which made me (“Ted”) Brodkin, MD, realize that it was possi- Assistant Professor of Psy- ble to be a psychiatrist, chiatry at University of but also to do basic neu- Pennsylvania. roscience research to better understand the Dr. Brodkin’s fascination fundamental neurobio- with the neurobiology of logical basis of behav- social behaviors dates to iors and psychiatric his Harvard undergradu- from left to right: disorders,” says Dr. ate years, when he studied Mary Calderone, Matthew Torre, Rhia Shah, Edward (“Ted”) Brodkin, Brodkin. Harry Harlow’s work. Andrew Fairless, Arati Sadalge Kreibich, Holly Dow “Although Harlow did not With this goal in mind, work on autism or schizophrenia, studying his he immersed himself in basic science work during groundbreaking work on the development of two postdoctoral research fellowships immediately attachment in infancy and childhood got me hooked following his residency. He first studied basic neu- on the field of social neuroscience in general,” Dr. robiology at Yale in the laboratory of Eric Nestler, Brodkin says. During his Psychiatry residency at MD, PhD and then genetics at Princeton in the labo- Yale, he began to treat adults with autism spectrum ratory of Lee Silver, PhD. In 2002, Dr. Brodkin disorders (ASD). joined the faculty in Penn’s Department of Psychia- try. “I found the issues these patients were dealing with uniquely compelling,” Dr. Brodkin recalls. “The dif- At Penn, Dr. Brodkin established a laboratory ficulties with social interactions that they faced focused on social neuroscience to investigate the were beyond the level of simply being shy or intro- neurobiology and genetics of social behavior dis- verted. It was extremely difficult or impossible for ruptions associated with ASD and schizophrenia. many of them to engage in the important activities It’s a fertile area for investigation. As in ASD, social of life that require navigating a social environment, behavior impairments in schizophrenia are extreme- such as functioning in school or work, shopping for ly disabling; the underlying neurobiology is poorly basic necessities, or forming new relationships, even understood; and current treatments are largely inef- if they were intellectually bright. This led to a great fective. While there are fairly effective treatments deal of hardship and suffering for both the patients for many of the so-called “positive” symptoms of Continued on page 4

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Continued from page 3 schizophrenia, such as hallucinations and delusions, behaviors. Dr. Brodkin identified a specific mouse available treatments are inadequate for treating the strain, the BALB/cJ strain, that shows low levels of “negative” or deficit symptoms, such as lack of inter- social interaction and other brain traits that may be est in social interaction. The long-term goal of Dr. relevant to ASD. In 2007, Dr. Brodkin secured a five- Brodkin’s work is to provide a neurobiological and year grant from the National Institute of Mental pathophysiological foundation for new treatment Health for a study entitled the “Neurobiology of approaches in both ASD and schizophrenia. Sociability in a Mouse Model System Relevant to Autism,” which is part of the NIMH’s new program Dr. Brodkin’s lab uses mouse models to analyze the in the Social Neuroscience of Mental Health. The neurobiological mechanisms of social behaviors rele- goal is to test the links among low sociability and vant to ASD and schizophrenia. The challenge lies in various brain traits in BALB/cJ mice. He is also developing etiologically valid animal models, i.e. models that show behavioral and brain traits that are attributable to the same genetic and/or environmen- tal factors that cause the disorders. At a biological “I would say for psychiatric illnesses, level, autism and schizophrenia are not each single and particularly for our understanding of diseases, but rather each comprises biologically het- social behaviors,” Dr. Brodkin acknowl- erogeneous groups of disorders. Because our under- edges, “we really are at a very early standing of the genetic and environmental causes of stage of our understanding. There’s a these disorders has been progressing more rapidly in recent years, developing etiologically valid mouse long way to go, but working toward bet- models is becoming possible. The mouse is used ter understanding of these disorders will because it is the leading model organism for study- be fascinating and will pay off in much ing mammalian genetics and for developing mam- better care for patients.” malian models of human disease. “For virtually every human gene, there is a mouse counterpart, and vice versa,” Dr. Brodkin says. “So, as we identi- studying social behaviors in mice with mutations of fy human disease genes, we can study them in mice, genes that have been linked with ASD or schizophre- and can develop mouse models of the disease.” nia. He is using these mouse models both to better “Although it may be impossible to model all symp- understand underlying brain mechanisms, and to test toms of ASD or schizophrenia, such as complex lan- novel pharmacologic treatment approaches. guage or higher order cognitive impairments, there “We are interested in either obtaining or making are certain basic behavioral components of the disor- mice with mutations in those genes,” Dr. Brodkin ders, such as reduction in a primal form of sociabili- explains, “and trying to understand the chain of ty (reduced seeking of social interaction), that we events that leads from particular gene mutations, to can observe and measure quantitatively in animals,” alterations in brain development and function, to Dr. Brodkin says. “We study animal models to try social withdrawal. And, finally, we will use these to understand the underlying biology on a deeper models as systems in which to test out new treat- level than would be possible in human studies alone. ments that would restore sociability. We are still at But this is done best in close collaboration with clini- very early stages in this endeavor, partly because the cal investigators, to make sure that the basic research genes and environmental factors that predispose cer- questions we are asking, and the answers we are get- tain individuals to ASD and schizophrenia are just ting, are as relevant as possible to human health. starting to be identified. We are also continuing to Ideally there is an ongoing, reciprocal interaction develop and refine the tools necessary to best under- between clinical and basic researchers, and I really stand the relevant phenotypes in mouse models. But have that here at Penn, which makes it a special it is a very exciting time, and the field as a whole place.” seems to be on the threshold of a great deal of Dr. Brodkin’s lab has identified regions of the mouse progress.” genome linked with social behavior phenotypes. In Dr. Brodkin also plans to examine the role that envi- genes within those genomic regions, his lab is study- ronmental factors play in the genesis of social behav- ing the effects of sequence variants (alleles) on social Continued on page 5 www.med.upenn.edu/psych PAGE 5 www.med.upenn.edu/psych

Continued from page 4 ior disruptions, work already underway in collabo- PhD and Christos Davatzikos, PhD in Radiology, ration with Michal Elovitz, MD in the Penn Depart- who contribute neuroimaging expertise. Dr. Brodkin ment of Obstetrics and Gynecology. “Dr. Elovitz has also collaborates extensively with Ted Abel, PhD in developed a mouse model of prenatal inflammation, the Department of Biology in the School of Arts and which appears to be a risk factor for ASD, so togeth- Sciences, Martha Farah, PhD and Seth Gillihan, PhD er we are studying the effects of prenatal inflamma- in the Department of Psychology, and Tracy Bale, tion on brain development and social behavior PhD in the Department of Animal Biology in the development,” he says. “We also plan to study the School of Veterinary Medicine. effects of gene-environment interactions on brain “I also want to highlight the work of the extremely and social behavior development.” bright and talented people in my lab, who deserve Dr. Brodkin’s lab is part of the Department’s initia- so much of the credit for our work, including Holly tive to better understand ASD, schizophrenia, and Dow, Geena Sankoorikal, Kristin Kaercher, Andrew other neurodevelopmental disorders. It comple- Fairless (a Penn neuroscience graduate student), and ments the work of the Adult Developmental Disor- Arati S. Kreibich, PhD (a postdoctoral researcher), as ders Program, directed by Anthony L. Rostain, MD, well as many Penn undergraduates who have made MA, which treats these disorders and conducts clini- significant contributions,” says Dr. Brodkin. cal research seeking improved treatments. Dr. Brod- “Being at Penn has benefited me in a lot of ways,” kin is an attending psychiatrist in that program. Dr. says Dr. Brodkin. “The Department of Psychiatry Brodkin’s lab research also complements the work of enables me to have this kind of career where I can the Neuropsychiatry division, which is focused on combine patient care with basic research. This is not schizophrenia and directed by Raquel Gur, MD. true of every Psychiatry department around the Dr. Brodkin explains that caring for patients informs country. And the level of interaction that is possible his research. “I enjoy working with patients with between faculty members at the medical school and ASD, and doing so focuses my research questions. the other schools of the University makes Penn real- Many of these patients can describe their subjective ly special.” experiences of social situations very articulately, Dr. Brodkin understands the formidable research which gives us important insight.” challenges that must be overcome to achieve an ”One of the best aspects of being at Penn is the ter- understanding of complex social behaviors relevant rific, collaborative research environment here,” Dr. to ASD and schizophrenia, but he also recognizes Brodkin says. Within the Department of Psychiatry, the potential rewards. “As Lewis Thomas wrote, the key collaborators include Wade Berrettini, MD, PhD, better we understand the basic pathophysiological who has been a mentor as well, Irwin Lucki, PhD, mechanisms of diseases, the more effective and Raquel Gur, MD, PhD, Ruben Gur, PhD, Steven affordable our efforts to treat the diseases can Siegel, MD, PhD, Chang-Gyu Hahn, MD, PhD, Gre- become. This is illustrated well by the progress gory Carlson, PhD, Steven Arnold, MD, Konrad Tal- made in treating and preventing many bacterial bot, PhD, Falk Lohoff, MD, David Mandell, ScD, infectious diseases in the 20th century.” Anthony Rostain, MD, MA, and Adrian Raine, PhD. “I would say for psychiatric illnesses, and particular- In the School of Medicine, collaborators include ly for our understanding of social behaviors,” Dr. Robert Schultz, PhD, a Professor in the Department Brodkin acknowledges, “we really are at a very early of Pediatrics and Director of Center for Autism stage of our understanding. There’s a long way to Research at Children’s Hospital of Philadelphia go, but working toward better understanding of (CHOP), who uses neuroimaging to identify specific these disorders will be fascinating and will pay off brain structural and functional abnormalities in in much better care for patients.” autism; Hakon Hakonarson, MD, PhD, who directs the Center for Applied Genomics at CHOP; Michal The journey may be challenging and protracted, but Elovitz, MD in Obstetrics and Gynecology, who if we have learned anything so far from Dr. Brodkin studies prenatal environmental factors in autism; and his laboratory’s approach to understanding the Maja Bucan, PhD in Genetics, who studies behav- basic neurobiology of social behaviors, that is more a ioral and psychiatric genetics; and Harish Poptani, source of inspiration than frustration.

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