3

GLIA

Neurons and Glial Cells

  • Definition: Neurons are cellular components of the nervous system.

  • Glial Cells: Types of glial cells include:

    • Astrocytes

    • Oligodendrocytes

    • Schwann Cells

    • Microglia

Astrocytes

  • History:

    • Discovered by Otto Deiters in 1860.

    • Name ‘astrocyte’ given by Mihaly von Lenhossek in 1895.

  • Main Functions:

    • Envelop blood vessels and neurons.

    • Provide metabolic support.

    • Facilitate transmitter uptake.

    • Participate in gliotransmission.

    • Reference: Figley & Stroma, 2011, European J Neurosci.

Capacity of a Single Astrocyte

  • A single astrocyte can wrap around up to 140,000 synapses in rodents and approximately 2 million synapses in humans.

Chemical Homeostasis and GLT-1

  • Importance of GLT-1:

    • GLT-1 (Glutamate Transporter 1): In rodents, analogous to GLAST (Glutamate Aspartate Transporter 1) in humans.

    • It eliminates over 80% of neuronal and glial extracellular glutamate, essential for preventing excitotoxicity.

  • Mechanism:

    • Found primarily in perisynaptic processes (astroglial processes near pre- and postsynaptic sites).

    • Approximately 75% of glutamate is recycled every 20 seconds.

    • Excess glutamate binds to neuronal glutamatergic receptors like:

    • Postsynaptic: NMDA-R and mGluR5.

    • Presynaptic: mGluR2/3 autoreceptors.

Metabolic Support by Astrocytes

  • Role of Astrocytes:

    • Primary producers of lactate, the main energy source for neurons.

  • Astrocyte-Neuron Lactate Shuttle:

    • Synaptic glutamate uptake via GLT-1 stimulates blood glucose transfer to astrocytes through glucose transporter 1 (GLUT1).

    • Glucose is converted into lactate and released back into the synapse for neuronal uptake via monocarboxylate transporters (MCTs).

    • Necessary for maintaining long-term potentiation (LTP) and overall neuronal excitability.

Excitatory Synapses

  • Uptake by Astrocytes:

    • GLT-1 and GLAST uptake synaptic glutamate, converting it into glutamine (a precursor for glutamate) and releasing it back into the synapse for neuronal glutamate production.

  • Conversion of Glucose:

    • Blood-derived glucose is converted into D-serine, which serves as the primary co-transporter for NMDA-R, maintaining glutamate homeostasis.

Inhibitory Synapses

  • Receptors Expressed by Astrocytes:

    • Astrocytes express GABA-A and GABA-B receptors.

  • Mechanisms:

    • GABA-B receptor stimulation activates astroglial calcium flux, leading to glutamate release.

    • Synaptic GABA uptake occurs via GABA transporters (GAT) 1 and 3.

    • GABA is converted into glutamine, released back into the synapse.

    • Notably, astrocytes have been shown to release GABA into synapses in certain regions like the thalamus, maintaining inhibitory tone.

Microglia

  • Description:

    • Microglia are small cells in the central nervous system (CNS), representing the resident immune cells (similar to macrophages) and constituting 10% of the brain cell population.

  • States of Microglia:

    • Homeostatic (resting): Characterized by actin-dependent filopodia which survey the local environment.

    • Reactive: Involves the release of both anti- and pro-inflammatory chemicals.

    • Functions include:

    • Inflammation.

    • Clearing debris.

    • Responding to environmental changes (toxins, drugs of abuse).

    • Learning-dependent neuroplastic adaptations.

Evolving Understanding of Microglia

  • Old View: Characterization based on dichotomies (good vs bad).

  • New View: Recognizes the coexistence of multiple states (e.g., Epigenetic, Activated M1/M2 states).

    • M1: Pro-inflammatory

    • M2: Anti-inflammatory

  • Multidimensional Integration: New approaches include transcriptomic and metabolomic analyses.

Discovery of Microglia

  • Early Observations:

    • 1899: Franz Nissl first reported rod-shaped cells in human cases.

    • 1913: Cajal provided the first morphological description of microglial cell bodies.

    • Pío del Río-Hortega is noted for significant methodological advancements for studying microglia.

  • Further Developments:

    • By 1966, it was established that rodent microglial cells can proliferate in response to nerve injury (facial nerve axotomy).

Functions of Reactive Microglia

  • Synaptic Plasticity: Microglia influence synaptic strength, though debate exists over direct vs. indirect influence.

    • Synaptic Weakening Mechanisms:

    • Activation of the complement system.

    • Dendritic secretion of phosphatidylserine.

    • Astrocyte release of IL-33.

    • Synaptic Preservation:

    • CD200 binding to microglial CD200R.

    • Neuronal release of CD47 and CD55, which blocks activation of the complement system.

Microglia and Synaptic Strengthening

  • New Dendritic Spine Head Formation: Associated with direct contact between microglia and dendritic spines, important for various behavioral tasks in rodents.

  • Plasticity Genes: Several genes related to neuroplasticity are tied to microglial reactivity and linked to LTP.

  • BDNF Release: Microglia release Brain-Derived Neurotrophic Factor (BDNF), vital for cortical plasticity, enhancing dendritic spine formation and aiding in memory and fear-related tasks.

Reactive Microglial Neuronal Regulation

  1. TLR4-MD2 Complex Activation: Stimulates an intracellular cascade resulting in pro-inflammatory and neurotrophic factor release.

  2. TNF-α Effects: Increases postsynaptic calcium-permeable AMPA-R, decreases GABA-AR.

  3. IL-1β Contribution: Influences LTP by modifying postsynaptic NMDA conductance.

  4. BDNF Role: Mechanism remains unclear; appears to increase GABAergic neuron excitability.

Interaction Between Reactive Microglia and Astrocytes

  • Astrocytic Response:

    • TNF-α: Downregulates astrocytic GLT-1 and facilitates astroglial glutamate release.

    • IL-1β: Also downregulates astrocytic GLT-1.

  • Communication: Under homeostatic conditions, astrocytes and microglia maintain synaptic stability via mutual interactions.

Myelinating Cells

  • Oligodendrocytes (OL): Located in the CNS, can myelinate multiple axons.

  • Schwann Cells: Located in the PNS, each myelinates only one axonal segment.

Importance of Myelin

  • Axonal Ensheathment: OL and Schwann cells form concentric compact layers of myelin around axons, termed internodes, which can vary in size and length.

  • Myelination Order: Larger axons are typically myelinated before smaller ones due to increased metabolic and conduction efficiency.

Oligodendrocyte Lineage Cells

  • Historical Context: Pío del Río Hortega published initial studies on oligodendrocytes in 1921; term 'oligodendrocyte' combines Greek roots meaning "few branches".

  • Three Cellular States:

    • Oligodendrocyte Precursors (OPCs)

    • Immature Pre-myelinating Oligodendrocytes

    • Mature Myelinating Oligodendrocytes

  • Diversity: Varied development, morphology, origins, and myelinating functions.

Transition from OPC to OL

  • Processes Involved:

    • Direct differentiation from OPCs into OLs.

    • Proliferation and death of OPCs.

    • Formation, extension, and retraction of new sheaths, along with existing remodelling.

OPC Functions

  • Active Role in Neuroplasticity:

    • OPCs express chondroitin sulfate proteoglycan NG2 channels and are involved in LTP modulation.

    • Glutamate release can stimulate post-synaptic AMPA/NMDA receptors, promoting LTP.

    • Kir4.1 channels in OPCs help maintain potassium balance in synapses, further stabilizing LTP.

Myelination by Oligodendrocytes

  • Mechanism:

    • Coupled with Nodes of Ranvier, supports saltatory conduction, enhancing action potentials.

    • Saltatory conduction occurs due to high-density voltage-gated sodium and potassium channels between nodes that recharge action potentials.

    • Myelination patterns can be adaptive, adjusting sheath thickness and node length as per axonal activity levels, improving metabolic support.

    • Example: Lactate transfer from myelin to axonal mitochondria prevents metabolic loss.

Oligodendrocytes and Synapses

  • Interactions with Neurons:

    • OL release of BDNF promotes presynaptic glutamate release which, in turn, stimulates further BDNF release via mGluR binding and TNF-R2 activation for myelination.

  • Astrocytic and Microglial Contributions:

    • TNFα interactions with OL receptors can yield both promoting and inhibiting outcomes for myelination.

    • Microglia play a role in clearing debris and fostering differentiation of OPCs into OLs while facilitating synaptic strength expression.

Future Topics

  • Next Week's Discussion: Ethics and research methods in clinical populations.

  • Key Questions:

    • Considerations when working with clinical populations.

    • Formulation of complex neuroscience questions using both clinical and preclinical models.