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.