Neuron-glial Cell Interactions in Biology and Disease >> Content Detail

Lecture Notes

Lecture Notes

Summaries of each lecture are provided below, along with the list of background papers used by the instructor to prepare each lecture.

1Overview of the class, introduction to glia and use of PubmedI will introduce the structure of the class: what you should expect, and what we will learn throughout the semester. I will give a brief introduction to glial cells and their interactions with the nervous system. We will also look into how one can access the scientific literature by using Pubmed and Google™ Scholar.
2Myelination in the peripheral nervous system (PNS): Schwann cells

The most abundant glial cell within the peripheral nervous system is the myelinating Schwann cell. The main function of myelination is to insulate neurons and facilitate neuronal conductivity along the output end of a neuron, i.e. the axon. Each myelinated region of a given axon is interrupted by a non-myelinated axon segment called a Node of Ranvier. The assembly of proteins to Nodes of Ranvier is essential in facilitating rapid and effective conduction of the neural signal and maintaining neuronal integrity. In this class, we will focus on how the Nodes of Ranvier are assembled into architecturally complex structures and how disruption of this assembly can lead to diseases like X-linked Charcot-Marie-Tooth (CMTX) disease. CMTX affects the sensory neurons of the PNS because of mutations within the coding region of the connexin-32 gene. Connexin-32 (Cx32) is a channel protein involved in the formation of gap junctions and mutations identified in CMTX impair the function of the channel. We will discuss why abnormalities resulting from mutations of Cx32 are limited to peripheral nerves, despite the wide spread distribution of the protein throughout the body.

Pedraza, L., J. K. Huang, and D. R. Colman. "Organizing Principles of the Axoglial Apparatus." Neuron 30, no. 2 (May 2001): 335-44. Review.

Goldberg, G. S., V. Valiunas, and P. R. Brink. "Selective Permeability of Gap Junction Channels." Biochim Biophys Acta 1662, no. 1-2 (March 23, 2004): 96-101. Review.

Suter, U., and S. S. Scherer. "Disease Mechanisms in Inherited Neuropathies." Nat Rev Neurosci 4, no. 9 (September 2003): 714-26. Review.

Jessen, K. R., and R. Mirsky. "The Origin and Development of Glial Cells in Peripheral Nerves." Nat Rev Neurosci 6, no. 9 (September 2005): 671-82. Review.

3Myelination in the central nervous system (CNS): Oligodendrocytes

Oligodendrocytes are responsible for myelinating axon fibers in the central nervous system. At the Nodes of Ranvier, clustering of sodium and potassium channels is highly regulated and occurs after myelination of the axon fibers. This week, we will study the underlying mechanisms of sodium channel clustering and will discuss the pathology of neurons in demyelinating disorders such as Multiple Sclerosis.

Poliak, S., and E. Peles. "The Local Differentiation of Myelinated Axons at Nodes of Ranvier." Nat Rev Neurosci 4, no. 12 (December 2003): 968-80. Review.

Waxman, S. G., M. J. Craner, and J. A. Black. "Na+ Channel Expression along Axons in Multiple Sclerosis and its Models." Trends Pharmacol Sci 25, no. 11 (November 2004): 584-91. Review.

Waxman, S. G. "Axonal Conduction and Injury in Multiple Sclerosis: The Role of Sodium Channels." Nat Rev Neurosci 7, no. 12 (December 2006): 932-41. Review.

4The Nogo hypothesis

Unlike PNS axons, severed axons of the CNS are unable to regenerate because of the presence of myelin-inhibitory factors, such as Nogo. The Nogo gene has three isoforms, Nogo A, B, and C. Nogo A is the form expressed in oligodendrocytes. We will discuss how Nogo inhibits axon regeneration in spinal cord injuries and talk about recent discoveries concerning therapeutic agents against Nogo A.

Harel, N. Y., and S. M. Strittmatter. "Can Regenerating Axons Recapitulate Developmental Guidance During Recovery From Spinal Cord Injury?" Nat Rev Neurosci 7, no. 8 (August 2006): 603-16. Review.

Lee, D. H., S. M. Strittmatter, and D. W. Sah. "Targeting the Nogo Receptor to Treat Central Nervous System Injuries." Nat Rev Drug Discov 2, no. 11 (November 2003): 872-8. Review.

Dimou, L., L. Schnell, L. Montani, C. Duncan, M. Simonen, R. Schneider, T. Liebscher, M. Gullo, and M. E. Schwab. "Nogo-A-Deficient Mice Reveal Strain-Dependent Differences in Axonal Regeneration." J Neurosci 26, no. 21 (May 2006): 5591-603.

5Neuregulin-1 and schizophrenia

Schizophrenia is a subtle disorder of brain development and synaptic function affecting 0.5-1% of the population worldwide. It is devastating in that it interferes with most basic cognitive processes: perception, emotion and judgment. An intriguing finding concerning the neuropathology of schizophrenia is that there is a reduction in the myelin content of the brain region associated with higher-order cognitive functions (i.e. the prefrontal cortex) and a misregulation of genes involved in myelination. Schizophrenia is a complex disease with multiple contributing genes and neurogulin-1 and its receptor erbB4 are two candidate genes linked to schizophrenia susceptibility. Data from diverse populations suggest that polymorphisms within the 5'-end of neuregulin-1 gene might lead to altered expression of the gene. This week we will discuss signaling pathways governed by Neuregulin-1 (NRG1) and its receptor erbB4, and how dysregulation of the NRG1-erbB4 signaling relates to the neuropathology of schizophrenia.

Freedman, R. "Schizophrenia." N Engl J Med 349, no. 18 (October 30, 2003): 1738-49. Review.

Morrison, P. D., and R. M. Murray. "Schizophrenia." Curr Biol 15, no. 24 (December 20, 2005): R980-4. Review.

Nave, K. A., and J. L. Salzer. "Axonal Regulation of Myelination by Neuregulin 1." Curr Opin Neurobiol 16, no. 5 (October 2006): 492-500. Review.

Corfas, G., K. Roy, and J. D. Buxbaum. "Neuregulin 1-erbB Signaling and the Molecular/Cellular Basis of Schizophrenia." Nat Neurosci 7, no. 6 (June 2004): 575-80. Review.

Ross, C. A., R. L. Margolis, S. A. Reading, M. Pletnikov, and J. T. Coyle. "Neurobiology of Schizophrenia." Neuron 52, no. 1 (October 5, 2006): 139-53. Review.

Taveggia, C., G. Zanazzi, A. Petrylak, H. Yano, J. Rosenbluth, S. Einheber, X. Xu, R. M. Esper, J. A. Loeb, P. Shrager, M. V. Chao, D. L. Falls, L. Role, and J. L. Salzer. "Neuregulin-1 type III Determines the Ensheathment Fate of Axons." Neuron 47, no. 5 (September 2005): 681-94.

Kondziella, D., E. Brenner, E. M. Eyjolfsson, and U. Sonnewald. "How Do Glial-Neuronal Interactions Fit Into Current Neurotransmitter Hypotheses of Schizophrenia?" Neurochem Int 50, no. 2 (January 2007): 291-301.

6Field tripFor this occasion, we visited the laboratory of Dr. Gabriel Corfas at the Children's Hospital, Harvard Medical School. Roy, Kristine, Dr. A postdoctoral fellow in the Corfas laboratory, presented us with her work on neuregulin signaling and discussed her recently published work entitled "Loss of erbB Signaling in Oligodendrocytes Alters Myelin and Dopaminergic Function, a Potential Mechanism for Neuropsychiatric Disorders." Proc Natl Acad Sci U S A 104, no. 19 (May 8, 2007): 8131-6.
7CNS Astrocytes, part I: Interactions with oligodendrocytes

Astrocytes are the second most common glia in the central nervous system. They have long been regarded as either merely providing nutritional support for neurons or serving as boundary elements functionally separating different regions of the brain. Within the past 20 years this view has been challenged by several findings, and astrocytes are now known as key players in neuromodulation, synaptogenesis, myelination and neurogenesis. In this session, we will discuss how astrocytes interact with oligodendrocytes to regulate myelination and how retroviruses can disrupt this interaction leading to demyelination in diseases such as Multiple Sclerosis.

Franklin, R. J. "Why Does Remyelination Fail in Multiple Sclerosis?" Nat Rev Neurosci 3, no. 9 (September 2002): 705-14. Review.

Fields, R. D., and G. Burnstock. "Purinergic Signalling in Neuron-Glia Interactions." Nat Rev Neurosci 7, no. 6 (June 2006): 423-36. Review.

Haydon, P. G. "GLIA: Listening and Talking to the Synapse." Nat Rev Neurosci 2, no. 3 (March 2001): 185-93. Review.

Demerens, C., B. Stankoff, M. Logak, P. Anglade, B. Allinquant, F. Couraud, B. Zalc, and C. Lubetzki. "Induction of Myelination in the Central Nervous System by Electrical Activity." Proc Natl Acad Sci U S A 93, no. 18 (September 3, 1996): 9887-92.

Stevens, B., and R. D. Fields. "Response of Schwann Cells to Action Potentials in Development." Science 287, no. 5461 (March 24, 2000): 2267-71.

8CNS Astrocytes, part II: Neuromodulation and Alzheimer's disease

Probably the most intriguing finding concerning astrocytes is that these cells can modulate neuronal activity within certain regions of the brain. The modification of neural activity by glia is essential in information processing and storage in the brain. In this class, we will learn about signaling mechanisms that allow astrocytes to communicate with neighboring neurons. We will also discuss how these signaling pathways in astrocytes can be switched from neuromodulation to neurodegeneration in diseases like Alzheimer's.

Nagele, R. G., J. Wegiel, V. Venkataraman, H. Imaki, K. C. Wang, and J. Wegiel. "Contribution of Glial Cells to the Development of Amyloid Plaques in Alzheimer's Disease." Neurobiol Aging 25, no. 5 (May-June 2004): 663-74. Review.

Leonoudakis, D., S. P. Braithwaite, M. S. Beattie, and E. C. Beattie. "TNFalpha-Induced AMPA-Receptor Trafficking in CNS Neurons; Relevance to Excitotoxicity?" Neuron Glia Biol 1, no. 3 (August 2004): 263-273.

Allan, S. M., and N. J. Rothwell. "Cytokines and Acute Neurodegeneration." Nat Rev Neurosci 2, no. 10 (October 2001): 734-44. Review.

9CNS Astrocytes, part III: Synaptogenesis and epilepsy

Abnormal synchronous neuronal activity is a hallmark of epilepsy. In postmortem epileptic brains, astrocytes display altered morphology and altered expression of proteins associated with their function. However, how astrocytes contribute to epilepsy is still debated. This week, we will discuss the developmental and functional contributions of astrocytes to epilepsy.

McNamara, J. O., Y. Z. Huang, and A. S. Leonard. "Molecular Signaling Mechanisms Underlying Epileptogenesis." Sci STKE 2006, no. 356 (October 10, 2006): re12. Review.

10CNS Astrocytes, part IV: The role of glial cells in adult neurogenesis

For many years, the adult brain has been considered to be solely a postmitotic organ, in which new neurons are not generated. Recently, this view has been challenged with the identification of neural stem cells within the adult brain. Knowing the function of neural stem cells in the adult brain may facilitate the understanding of the development of treatments for neurodegenerative disorders. This week we will explore how glial cells contribute to the regulation of neurogenesis.

Gross, C. G. "Neurogenesis in the Adult Brain: Death of a Dogma." Nat Rev Neurosci 1, no. 1 (October 2000): 67-73. Review.

Goldman, S. "Glia as Neural Progenitor Cells." Trends Neurosci 26, no. 11 (November 2003): 590-6. Review.

Ming, G. L., and H. Song. "Adult Neurogenesis in the Mammalian Central Nervous System." Annu Rev Neurosci 28 (2005): 223-50. Review.

Hagg, T. "Molecular Regulation of Adult CNS Neurogenesis: An Integrated View." Trends Neurosci 28, no. 11 (November 2005): 589-95. (Epub September 8, 2005). Review.

Kimelberg, H. K. "The Problem of Astrocyte Identity." Neurochem Int 45, no. 2-3 (July-August 2004): 191-202. Review.

11CNS Astrocytes, part V: Gliomas

Glial and neuronal cells derive from common progenitor cells during development. Dysregulation of the signaling pathways in glia may result in tumorigenesis within the brain. Although they occur rare among all known malignant tumor, glial brain tumors are extremely hard to treat and can cause lethality within months after diagnosis. This week we are going to learn how brain tumor cells bear similarities to normal neurons and glia. Learning about physiological properties of glial tumor cells may help specific drug design for treatment of this devastating disease of glioblastoma.

Zhu, Y., and L. F. Parada. "The Molecular and Genetic Basis of Neurological Tumours." Nat Rev Cancer 2, no. 8 (August 2002): 616-26. Review.

Anderson, C. M., and R. A. Swanson. "Astrocyte Glutamate Transport: Review of Properties, Regulation, and Physiological Functions." Glia 32, no. 1 (October 2000): 1-14. Review.

12Microglia of the CNS

The last but not the least type of glia in the nervous system is called microglia. These cells are known as the immune cells of the nervous system, because of their neuroprotective role and their ability to release cytokines in response to neuronal injury. This week we will consider two different neurological diseases associated with activated microglia: HIV-associated dementia in the brain and neuropathological pain in the spinal cord.

Block, M. L., L. Zecca, and J. S. Hong. "Microglia-Mediated Neurotoxicity: Uncovering the Molecular Mechanisms." Nat Rev Neurosci 8, no. 1 (January 2007): 57-69. Review.

Gonzalez-Scarano, F., and J. Martin-Garcia. "The Neuropathogenesis of AIDS." Nat Rev Immunol 5, no. 1 (January 2005): 69-81. Review.

132nd assignment: Oral presentations


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