M

Glia Function in Neuroscience

General Information

  • The lectures will cover the function of glia in neuroscience.

  • The slides are available online.

  • Rules of engagement:

    • Communication is encouraged.

    • Ask questions if anything is unclear.

    • The lectures present the state of the art, not universal truth.

    • Alternative explanations will be provided.

    • It is up to the student to elaborate with additional reading.

    • The lecturer may be wrong about some things.

    • Take notes and ask questions.

Purpose of the Lectures

  • To challenge the neurocentric view and highlight the importance of glia.

  • To give examples of why glia are the somewhat forgotten cells when we understand the complexity and the function of the brain.

  • Many historical and contextual reasons exist for the neurocentric view of neuroscience.

  • The lecturer's hidden purpose is to inspire interest and passion for glia.

Overview of Topics

  • Development of different glial cell types and their lineages.

  • Interconnection of glial cell development with brain development.

  • Specific functions of each glial cell type.

  • Relevance of glial cell dysfunction in brain disorders.

Methodological Considerations

  • Methods used in glial research differ from those used in neuron studies.

  • Action potential recordings are not common in glial research.

  • The lecturer will explain the methods used in glial research.

Learning Outcomes

  • Understand the development of glia, including timing and steps.

  • Understand the functions of glia in the brain environment, both in steady state and in the adult and aging brain.

  • Identify critical molecules and steps for the specification of specific glial cells.

  • Explore the role of glia in aging and disease.

  • Explore diseases particularly linked to the function of a given glial cell type.

Relation to Future Modules

  • The content will be continued in the neurodegenerative diseases module next year.

  • This module covers pieces not only for glia but for just generally neurodegenerative diseases.

Classification of Glial Cells

  • Microglia ethics tissues name: means the opposite.

  • Microglia: a specific type of glial cell.

  • Glia: everything that is not microglia.

Glial Cells Essential for Nervous System Function

  • Glial cells essential for development and function neurons, despite not carrying synaptic input.

  • Neurons comprise only 10% of cells in the central nervous system, while glia make up 90%.

  • The high percentage of glia suggests their critical role in brain function.

  • In the peripheral nervous system, Schwann cells are the main glial cell type.

  • In the central nervous system:

    • Microglia constitutes 10-15% of glia.

    • Astrocytes are the majority within microglia.

    • Ependymal cells and oligodendrocytes are also present.

    • Astrocytes are the most abundant cells in the brain.

Main Broad Functions of Glia

  • Provide physical support to neurons.

  • Supply nutrients and oxygen to neurons.

  • Insulate neurons, facilitating synaptic communication.

  • Destroy and remove cell debris and waste.

  • Critical developmental roles.

  • Participate in global migration.

  • Participate in the growth and direction of axons and dendrites.

  • Modulate synaptic transmission directly (astrocytes) or indirectly (microglia).

  • Critical role in brain disease and degeneration.

Interesting Numbers and Comparisons

  • The percentage of glia increases with the complexity of brain function across species.

  • Glia to neuron ratio is unbalanced, with more glia in complex brains.

  • Astrocytes in humans are larger than those in rats, allowing for greater signal integration.

  • The increase in neuron size is not proportional to the increase in the size of the astrocyte.

Historical Perspectives

  • The period of 70 years is considered the golden age of glial research.

  • Discoveries were driven primarily by improvements in technology.

  • Being a neuroscientist meant being an anatomist, using staining techniques and microscopy.

  • Rudolf Virchow (1856) first described glia, calling them glue (glia in Greek).

  • Otto Dieter described functional characteristics, noting the lack of axons in glia.

  • Debate focused on developmental origin, with Dieter suggesting a similar origin to neurons.

  • Subdivision of glia into different types occurred, with varying theories on their origin.

  • Ramón y Cajal postulated different types of glia from the ectoderm, identifying a third element.

  • del Río-Hortega challenged Ramón y Cajal, proposing four types of glia.

Del Río-Hortega's Discoveries

  • Proposed two types of glia in white matter and one in grey matter.

  • Identified mesodermal microglia.

  • Named them microglia for the first time, and he said that they would derive from the mesoderm.

  • He called another type of glia, which is what we know these days as oligodendrocytes.

  • This contradicted Ramón y Cajal, causing him to leave Spain until his discoveries were proven correct.

  • Functions such as plasticity, electrical insulation, and roles in pathology were attributed to glia.

  • After this golden era, there was a gap in glial research until the 1980s and 1990s.

  • From the 2000s onward, glia research regained attention due to the significant knowledge gap.

Traditional View of Glial Cell Development

  • Based on historical perspectives, the ectoderm gives rise to the neuroepithelium, which forms the brain.

  • From the neuroepithelium, neuroblasts give rise to neurons.

  • Glial blasts were thought to have bipotent capacity to generate astrocytes and oligodendrocytes.

  • The neuroepithelium also generates ependymal cells.

  • Astrocytes can specialize into different types depending on brain region and function.

  • Microglia were believed to derive from the mesoderm, originating from a missing old cell in the janitor.

  • These entered the brain and completed the picture.

Current Understanding of Glial Cell Development

  • It is uncertain whether all cells derive from a single astrocyte progenitor.

  • The diversity of astrocyte states is not fully understood.

  • In what is known: Microglia do not derive from the mesoderm- acc primitive myeloid progenitors?

Summary of Glial Cell Types and Functions

  • In the central nervous system:

    • Oligodendrocytes

    • Astrocytes

    • Microglia

  • Ependymal cells are also present.

  • In the peripheral nervous system, Schwann cells are the main type.

  • They follow a very similar developmental stepwise development as oligodendrocytes do.

  • Satellite cells are glial-like cells in the dorsal root ganglion.

Timing of Developmental Milestones

  • Brain and embryo development involves complex interactions between organs and systems.

  • Embryonic layers (ectoderm, mesoderm, endoderm) differentiate into various organs.

  • The embryo is connected to the yolk sac, which is important for glial cell development.

  • Myelination and synaptic pruning continue into late life.

  • Glia become important when neurons start connecting, except for microglia, which arrive earlier.

  • Microglia arrive around eight weeks post-conception, before the blood-brain barrier closes.

Specific Lineages

  • The neuroepithelium generates neuronal stem cells and glial stem cells.

  • These stem cells share a common progenitor, allowing for the generation of both glia and neurons.

  • Radial glia, found in layered structures like the cortex, serve as a scaffold for neurons.

  • Radial glia also have the ability to generate astrocytes.

Derivation of Astrocytes and Oligodendrocytes

  • A neuroepithelial stem cell (e.g., radial glia) can generate any cell in the brain.

  • From that stem cell, you will generate what is called an oligodendrocyte progenitor.

  • From an oligodendrocyte progenitor, it will start to cycle, it will start to replicate, and the cells that it will produce will be terminally differentiated into astrocytes.

  • The oligodendrocyte progenitor converts into an NG2 cell (expressing NG2 molecule).

  • NG2 cells persist into the adult brain and can reactivate to produce mature oligodendrocytes.

Oligodendrocyte Development

  • NG2 progenitors transition to immature oligodendrocytes (losing NG2 expression, expressing O4).

  • Immature oligodendrocytes progress to a mature oligodendrocyte state.

  • Mature oligodendrocytes express myelin proteins like GC or MBP.

  • Transcription factors like Notch1 and Prox1 regulate these transitions. when lose expressiob if notch1 get increase of prox1

  • The NG2 cells express high levels now survive into the adult brain and they can produce more astrocytes.

    • Notch1

    • Prox1

Schwann Cell Development

  • Schwann cells are related to oligodendrocytes, sharing functions in the peripheral nervous system.

  • They develop similarly, starting from neuroepithelial cells to Schwann cell precursors and immature Schwann cells.

  • There are myelinating and non-myelinating Schwann cells.

  • Myelinating Schwann cells contain the axon within their cytoplasm and wrap it with extensions.

  • Non-myelinating Schwann cells provide trophic support for neighboring axons and neurons.

Astrocyte Development

  • Astrocytes transition from neural stem cell progenitors to astrocyte precursors and mature astrocytes.

  • Mature astrocytes express proteins essential for function, such as GFAP.

  • Specific pathways define these transitions, with Sox9 essential for stem cell to astrocyte precursor transition.

  • Activation of the Jak-Stat pathway is critical for terminal differentiation.

  • There is functional and morphological heterogeneity in astrocyte populations.