Molecular Biology Faculty
Lisa M. Boulanger
Lewis Thomas Lab, 123
Lab (609) 258-4724
Immune proteins in the formation, function, and modification of neuronal connectivity
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 that 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. Furthermore, MHC expression in the brain is dynamic and is regulated by electrical activity in developing and adult circuits.
We and others have found that remarkably, these traditionally immune molecules remarkably 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, while 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 numerous genetic and biochemical tools have already been developed 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 expression 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.
Dixon Salazar TJ, Fourgeaud L, Tyler CM, Pole JR, Park JJ, Boulanger LM (2014) MHC class I limits hippocampal synapse density by inhibiting neuronal insulin receptor signaling. The Journal of Neuroscience. 34: 11844-11856. PubMed
Nelson PA, Sage JR, Wood SC, Davenport CM, Anagnostaras SG, Boulanger LM. (2013) MHC class I immune proteins are critical for hippocampus-dependent memory and gate NMDAR-dependent hippocampal long-term depression. Learn Mem. 20: 505-17. PubMed
Chacon MA, Boulanger LM. (2012) MHC class I protein is expressed by neurons and neural progenitors in mid-gestation mouse brain. Mol Cell Neurosci. 52: 117-27. PubMed
Tyler CM, Boulanger LM. (2012) Complement-mediated microglial clearance of developing retinal ganglion cell axons. Neuron. 74: 597-99. PubMed
Fourgeaud L, Davenport CM, Tyler CM, Cheng TT, Spencer MB, Boulanger LM. (2010) MHC class I modulates NMDA receptor function and AMPA receptor trafficking. Proc Natl Acad Sci. 107: 22278-83. PubMed
Fourgeaud L, Boulanger LM. (2010) Role of immune molecules in the establishment and plasticity of glutamatergic synapses. Eur J Neurosci. 32: 207-17. PubMed
Boulanger LM. (2009) Immune proteins in brain development and synaptic plasticity. Neuron. 64: 93-109. PubMed
Fourgeaud L, Boulanger LM. (2007) Synapse remodeling, compliments of the complement system. Cell. 131: 1034-36. PubMed
Boulanger LM, Shatz CJ. (2004) Immune signaling in neural development, synaptic plasticity, and disease. Nature Rev Neurosci. 5: 521-31. PubMed
Boulanger LM. (2004) MHC class I in neuronal development and plasticity. Neuron Glia Biol. 1: 283-89. PubMed
Belmonte MK, Allen G, Beckel-Mitchener A, Boulanger LM, Carper R, Webb SJ. (2004) Autism and abnormal development of brain connectivity. J Neurosci. 24: 9228-31. PubMed
Boulanger LM, Huh GS, Shatz CJ. (2001) Neuronal plasticity and cellular immunity: shared molecular mechanisms. Curr Opin Neurobiol. 11: 568-78. PubMed
Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM, Shatz CJ. (2000) Functional requirement for class I MHC in CNS development and plasticity. Science. 290: 2155-59. PubMed
Boulanger LM, Poo M-M. (1999) Gating of BDNF-induced synaptic potentiation by cAMP. Science. 284: 1982-84. PubMed
Boulanger LM, Poo M-M. (1999) Presynaptic depolarization regulates neurotrophin-induced synaptic potentiation. Nature Neurosci. 4: 346-51. PubMed
Boulanger LM, Lombroso PJ, Raghunathan A, During MJ, Wahle P, Naegele JR. (1995) Cellular and molecular characterization of a brain-enriched protein tyrosine phosphatase. J Neurosci. 15: 1532-44. PubMed