Lisa Boulanger
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Our laboratory is interested in how
proteins of the immune system participate in normal brain development
and
synaptic plasticity. We are particularly interested in members
of the major histocompatibility complex (MHC) class I,
a family of proteins which allow T cells to recognize and destroy
infected or cancerous cells. Although neurons were once thought
to be invisible to immune surveillance (“immune privileged”)
due to an apparent lack of MHC class I, recent studies have shown
that normal, healthy neurons can and do express MHC class I (see
figure below). Furthermore, MHC expression in the brain is dynamic
and is regulated by electrical activity in developing and adult
circuits.
Remarkably, we and others have found that these traditionally
immune molecules also perform crucial, non-immune functions in the brain. In
the visual system, MHC class I is required for activity-dependent refinement
of developing connections into their final, mature pattern. In the adult hippocampus,
MHC is required for normal long term potentiation (LTP) and long-term
depression (LTD), forms of activity-dependent synaptic plasticity thought
to underlie learning and
memory. There are dozens of MHCs and MHC-like proteins in 
the mammalian genome,
but for the majority, their functions remain largely unknown. The overall goal
of research in this laboratory is to identify neuronal functions of MHC, and
to characterize the cellular and molecular mechanisms by which MHC signals in
neurons.
To do this, we use a combination of single-cell patch
clamp and field electrophysiology, protein biochemistry, molecular genetics,
behavioral analysis, and microscopic imaging techniques. We also study the expression
of MHC class I in vitro and in vivo at the protein and mRNA
level. We are fortunate in that immunologists have developed numerous genetic
and biochemical tools for characterizing MHC class I expression and function
in the immune system. We are now applying these tools to the study of MHC class
I in the developing and adult brain.
Role in neurodevelopmental and neurodegenerative disorders
A long-term goal of the lab is to explore the implications
of neuronal MHC class I for human health and disease. Neurons expressing MHC
class I may be selectively vulnerable to autoimmune attack; intriguingly, the
neurons of the substantia nigra, which are specifically lost in Parkinson’s
disease, express high levels of MHC class I in the adult. Our recent studies
also suggest that disruptions of MHC class I expression or signaling could affect
normal brain development and plasticity.
One focus is on autism. Numerous previous reports have
suggested a symptomatic and genetic link between autism and the immune system,
and viral infection in the second trimester of pregnancy dramatically increases
the risk of autism in the child, yet the source of these associations remains
unclear. We are examining mouse models of autism to determine the role, if any,
for neuronal MHC class I in the origins of this disorder and the expression of
its symptoms.
Characterizing the role of immune molecules in the brain will expand our understanding of normal neural development, synaptic plasticity, and neural-immune interactions. We also hope that this research will suggest novel approaches to the diagnosis, treatment, and prevention of neurological disorders.
Boulanger L.M. and Shatz C.J.
(2004). Immune signaling in neural development, synaptic plasticity,
and disease. Nature Reviews Neuroscience 5:521-531.
Anderson G.M., Beckel-Mitchener A., Belmonte M.K., Boulanger L.M., et al. (2004). Autism as a disorder of neural information processing: directions for research and targets for therapy. Molecular Psychiatry 9:646-663.
Boulanger L.M., Huh, G.S., Shatz, C.J. (2001). Neuronal plasticity and cellular immunity: shared molecular mechanisms. Curr Opin Neurobiol 11:568-578.
Huh G.S., Boulanger L.M., Du H., Riquelme P.A., Brotz T.M., and Shatz C.J. (2000). Functional requirement for class I MHC in CNS development and plasticity. Science 290: 2155-2159.
Boulanger L.M. and Poo M.-m. (1999). Gating of BDNF-induced synaptic potentiation by cAMP. Science 284: 1982-1984.
Boulanger L. M. and Poo M-m. (1999). Presynaptic depolarization regulates neurotrophin-induced synaptic potentiation. Nat. Neurosci. (2)4: 346-351.
Boulanger L. M. , Lombroso, P.J., Raghunathan, A., During, M.J., Wahle, P., and Naegele, J.R. (1995). Cellular and molecular characterization of a brain-enriched protein tyrosine phosphatase. J. Neurosci., 15(2): 1532-1544.
Dr. Boulanger received her Ph.D. in Biology from UCSD in 1999 after working in the laboratory of Dr. Mu-ming Poo. She conducted postdoctoral research with Dr. Carla Shatz at Harvard Medical School, where she was the recipient of a Junior Fellowship from the Harvard Society of Fellows. Dr. Boulanger joined the faculty in 2004 and is currently an Alfred P. Sloan Research Fellow and Silvio Varon Professor of Neuroregeneration.
