Neuroimmunology, Brain Development, and Mental Disorders
Meeting Summary: October 02, 2008 – October 03, 2008
National Institute of Mental Health (NIMH)
In October 2008, the NIMH convened a multidisciplinary workshop to review recent findings on the role of neuroimmunologic mechanisms in normative neurodevelopment, and in the development of mental disorders. Participants considered a) evidence of a role of immune activation and/or dysfunction in mental disorders; b) disease models for understanding the role of immune and/or autoimmune responses in altering neurodevelopment; and, c) mechanisms of neuroimmunologic influences on development. Participants discussed major trends, methodological challenges, and opportunities.
Participants reviewed the evidence that neuroimmunologic factors, through in utero exposure to an infectious agent or to a maternal immune response, may place the offspring at risk for a range of atypical developmental outcomes including autism, schizophrenia, cognitive disabilities, and cerebral palsy. Epidemiological and clinical data, animal models, and postmortem neuropathological findings provide strong evidence that infection and inflammation are risk factors for adverse outcomes including atypical development and mental disorders. Several unanswered questions remain, as well as methodological challenges to overcome, before researchers can fully understand the biological mechanisms involved.
For example, questions remain about the specificity of an infection to a particular outcome. There may be different mechanisms and outcomes depending on whether inflammation exerts its effects at a single point in time or as a chronic process. Is it the infectious agent, the mechanism (e.g., altered myelination), or the timing of the exposure that differentiates outcome? What gene x environment x development interplay is involved? What protective mechanisms are involved? How might systemic acute or chronic immune responses alter immune molecules on neurons to alter connectivity, and thereby cause mental disorders?
Discussion focused especially on potential mechanisms by which immune factors might mediate neurodevelopment. Workshop participants discussed recent and ongoing experiments including investigations of the role of immune proteins in synaptic plasticity in developing and adult mammalian brains; immune activation models in rats and mice exploring the effects of prenatal immune activation; the use of a mouse model to explore mechanisms accounting for male vulnerability to developmental abnormalities associated with prenatal stress; and, a non-human primate model to test the hypothesis that maternal antibodies from the blood sera of some women may be reactive with fetal brain proteins.
Several methodological challenges currently hinder studies of the effects of prenatal immune exposure on developmental processes in animal models. There are parallels between the stress axis and immune activation, and it can be difficult to differentiate between the two mechanisms. Parenting behavior may be a confounding factor; participants suggested using cross-fostering models. Given that there are sex differences in the prevalence and/or age of onset in mental disorders, researchers should consider sex differences in experimental animal models. In addition, researchers could further explore the role of epigenetic regulation, and in particular the epigenetic machinery of the placenta. Participants suggested that the use of genetically-engineered animals or those with known genetic or environmental risk factors, as opposed to particular behavioral profiles, may be a better model for understanding neurodevelopment and for screening therapeutics. The lack of noninvasive techniques for detecting neuroinflammation has presented a challenge, but recent advances in PET may increase the feasibility of detecting and quantifying inflammation in the human and animal brain in vivo.
Workshop participants noted several gaps in our understanding of normative neuroimmunological development in humans and animals. For example, participants noted the need for cytokine and chemokine profiles for a variety of experimental animals. Researchers need established control values which are gender-, race-, age-, and ethnicity-specific in humans and animal models for cytokines and chemokines, as well as for cellular and serum markers. A more complete understanding of the neuroimmunologic mechanisms underlying synaptogenesis and synaptic elimination is needed as well. Recent technological advances in array tomography may help increase our understanding of these mechanisms.
In summary, workshop participants reviewed research on the role of neuroimmunologic factors in brain development and mental disorders. New findings suggest that this field holds promise for understanding the mechanisms underlying altered developmental trajectories and the emergence of mental disorders, and ultimately holds promise for the development of more effective treatment and prevention. The productive interactions among basic, preclinical, and clinical researchers resulted in several suggestions for continuing such discussions and for facilitating new collaborations.
For more information, please contact Ann Wagner, Ph.D., 301-443-5944.