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Neuroimmune Researchers Funded by Cure Autism Now Chosen to Give Public Forum Lecture on Autism

Autism reaches the mainstream of basic science research in neurochemistry
October 14, 2007


The American Society for Neurochemistry (ASN) addressed autism this year at its annual conference, which was held this June in Madison, Wisconsin. Two Cure Autism Now funded researchers, Dr. Carlos Pardo of John's Hopkins University and Dr. Lisa Boulanger of the University of California, San Diego, were invited to be keynote speakers in the ASN's public forum, a segment of the annual conference offered to raise public awareness about ongoing research in the field of neuroscience. Dr. Pardo and Dr. Boulanger spoke about their research involving immune mechanisms in autism to an audience mostly comprised of parents of children living with the disorder.

Dr. Pardo's presentation focused on his research that examines the role of neuroinflammation in the pathogenesis of autism. Studies in his laboratory involve use of post-mortem human brain tissue that compared the differences between brain tissue from autistic individuals and brain tissue from normal controls on a cellular level. Dr. Pardo and colleagues found that two important cell types, microglia and astroglia, were activated in the autistic brain tissue. Both microglia and astroglia, which are only found in the brain, serve as support cells for neurons and also mediate immune responses in the central nervous system. When activated these cells secrete chemicals called cytokines that can either stimulate or inhibit further inflammation.

Dr. Pardo also spoke about another facet of his research involving the examination of cerebral spinal fluid (CSF) of living patients. When comparing the CSF of autistic individuals to CSF from normal controls Dr. Pardo found that autistic people had higher levels of pro-inflammatory cytokines (cytokines that stimulate inflammation) than normal controls. Interestingly, pro-inflammatory cytokines were detected at higher levels in autistic individuals regardless of age, a finding that Dr. Pardo suggests may indicate that the inflammatory process in autism continues into adulthood. Although these are extremely important observations, Dr. Pardo also explained that the role of neuroinflammation in autism is not yet understood. For instance, it is not known whether the inflammation observed in the brain and CSF of autistic patients actually participates in causing autism, or whether it is a compensatory reaction to having autism. Dr. Pardo also cautioned that we don't know whether the neuroinflammation is a protective response or a harmful mechanism that further promotes the symptoms of autism. For these reasons, understanding the role of inflammation in autism remains a research priority. Dr. Pardo and colleagues are currently designing additional studies characterizing the CSF from autistic individuals to more specifically address the role that neuroinflammation plays in the development of autism. Finding people to participate in the studies will be crucial to their success. Individuals interested can contact Dr. Pardo directly at
cpardo@jhmi.edu.

Dr. Pardo's CAN-funded studies on neuroinflammation have also attracted the attention of the environmental science community. Dr. Pardo has been invited to speak about neuroinflammation and the pathogenesis of autism at a National Institute of Environmental Health Sciences (NIEHS) conference in September that will focus on the environment and neurodevelopmental disorders, including autism. The NIEHS is the branch of the National Institutes of Health devoted to environmental health and environment-related diseases.

More information about this conference can be found at
http://www.neurotoxicology.com/conference.htm


Dr. Boulanger's research also examines the role of the immune system in autism. At the public forum, Dr. Boulanger presented her work on how changes of a specific protein of the immune system, called MHC-I, can affect brain development and function. Dr. Boulanger actually started her career in neuroscience studying how brain circuitry is formed, and became interested in the role of immune signaling in the normal development of the brain. She began working on autism after learning of recent studies that linked autism to alterations in genes of the immune system and immune responses. Dr. Boulanger now hypothesizes that since MHC-I likely has a role in brain development and function, it may be altered in autism.

In her laboratory, Dr. Boulanger uses genetically altered mice that are deficient in MHC-I expression to address this important research question. Until recently, MHC-I proteins were not even thought to exist in neurons. Dr. Boulanger and colleagues have since demonstrated that normal, healthy neurons do make MHC-I. Interestingly, areas of the brain that are undergoing a late developmental step involving the formation of precise neuronal connections (a process that requires the removal of inappropriate connections) contain particularly high levels of MHC-I. Even though brain remodeling occurs throughout your lifetime, the peak period of sculpting neuronal connections is during early postnatal life. This is the time in which children with autism have been found to have increased brain sizes. Therefore, given what is known about brain overgrowth in autism, Dr. Boulanger and others have postulated that unusual strategies for locomotion, oversensitivity to light, sounds and smells may result from a failure to remove inappropriate neuronal connections which occurs during the normal development of the brain.

By using the eye as a model system and an innovative technology that allows tracking of individual neurons from the eye as they reach targets in the brain, Dr. Boulanger found visual inputs in mice without MHC-I make imprecise connections. These data suggest a critical role for MHC-I in the early development of the visual system and possibly other parts of the brain that use similar mechanisms to achieve perfect wiring. With her CAN grant, Dr. Boulanger is now focusing on the exact role of MHC-I in the remodeling process, and on what factors can influence the expression and function of MHC-I in the developing brain, hoping that this will provide guidance as to what processes may be affected in autism. Dr. Boulanger is also currently examining a mouse model developed by Dr. Paul Patterson at the California Institute of Technology (Caltech). When these mice are exposed to immune challenges during the fetal and postnatal period the mice go on to develop macrocephaly (large brains) and other brain structure abnormalities reminiscent of those seen in autism. Dr. Boulanger hopes that all of this work will shed light on the crucial and not-well understood link between immune system activation and brain circuit formation, an interaction that may be important to the development of autism.

Although the clinical link between Dr. Pardo's and Dr. Boulanger's work is evolving, it is believed that the expression of MHC-I in the brain is regulated by cytokines. Both researchers hypothesize that immune challenges that occur early in fetal and postnatal period can affect cytokine expression and may lead to abnormal brain development. Dr. Pardo's results suggest that there is a role for cytokines and inflammation in the pathogenesis of autism. Dr. Boulanger's results raise the possibility that immune challenges (such as a viral infection) may also be changing levels of MHC-I proteins in the brain, potentially offering an important link between immune system activation and brain wiring. They both caution, however, that the link between autism and inflammation is preliminary and may only be relevant in a subset of patients. Finally, although this work will hopefully have implications for treatment strategies, they both note that many current medications we know as being "anti-inflammatory" for the body may not also affect inflammation in the brain.

The excellent work of these two CAN-funded researchers suggests a strong role for the immune system in the pathogenesis of autism. Their research presents exciting new opportunities for additional studies that will investigate the role of inflammation, cytokines, and immune proteins such as MHC-I in the development of this disorder. A critical result of these CAN funded studies is that both Dr. Boulanger and Dr. Pardo are currently collaborating with many other research scientists in the immune community. Their work has stimulated a growing interest in the scientific community about how the neuroimmune system is involved in autism, thereby pushing the study of autism further into the mainstream of basic science research. Dr. Pardo enthusiastically thanked Cure Autism Now, stating that "we were having difficulty finding funding for our novel ideas - it wasn't until Cure Autism Now supported our research that we were able to explore the link between neuroinflammation and autism."

Cure Autism Now congratulates Dr. Pardo and Dr. Boulanger on their work and for being chosen to speak in such an important public forum.