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glia 2 Flashcards
Role of glia in;
- Development
- “Normal” mature CNS and PNS
- Aging
- Pathology and injury
importance of astrocytes
No functional neuronal activity without association by astrocytes
what are astrocytes for
- variation,
- Synaptogenesis/synaptic modulation,
- Blood brain barrier
(BBB), - Gap Junctions,
- Glutamate & GABA metabolism,
- Potassium buffering
micro glia are for
as neuro-immune modulators
gliosis
Reactive astrocytes and microglia in gliosis
Glial cell differentiation-CNS
Neural precursor cells (NPCs) generate neurons, then glia
Timing of this switch is crucial for determining number of neurons and glia in each brain region
- Extrinsic cues
(e.g. Wnt and Notch signalling) - Intrinsic cues
(e.g. Epigenetic changes; decrease neurogenic and increase astrogenic)
Astrocytes born BEFORE
oligodendroglia
Oligodendroglial function
myelination even occurring into 20’s in humans
Different parts of white matter mature at
different rates (males vs females also)
Astrocytes earlier than oligodendrocytes as are more
critical for establishment
Astrocyte specification = 5
- Still unclear how immature cells acquire all
characteristics of mature astrocytes in CNS - No knockout mutants or astrocyte specific
transcription factors - Gene expression studies
- Improved astrocyte markers (GFAP)
- Different glial subpopulations appear to be as different to one another as to neurons….
astrocyte variation:
Several major types;
According to morphology and spatial organization:
Cellular subtypes may differ not only phenotypically but also functionally
Radial astrocytes
surrounding ventricles
protoplasmic astrocytes
gray matter
fibrous astrocyte
white matter
bergmann glia (astrocyte)
cerebellum
velate astrocytes
granule layer of cerebellum
interlaminar astrocytes
supragranular layers of cerebral cortex
Astrocytes:Influences on axon & dendritic growth
dopaminergic neurons cultured on different astrocyte populations
- Depends on astrocyte population in vitro
- B-D
Cultured on
striatal astrocytes
(basal ganglia -
- where neurons grow to)
E-G - Cultured on
mesenchephali
c astrocytes
(midbrain - where neurons sit)
Astrocytes - synaptogenesis
- RGCs or cerebellar neurons cultured in absence of glia:
- Little synaptic activity
- Structurally defined synapses – usually poor
- Addition of glia
- Increases frequency/size of mEPSCs
- Decreases failure rate of evoked transmission
- Increases number of synapses
- Astrocytes may also modulate maturation of synapses
- Distribution of synapses alters – more organised
- Possible role in synapse removal (with microglia)
- Active participants in development and plasticity of dendritic spines and
synapses
blood brain barrier
Diffusion barrier impeding influx of molecules on basis of polarity and size, allows oxygen and hormone entry
while preventing passage of other molecules due to possible harmful effects
Astrocytes - blood brain barrier (BBB)
- High activity –
High glucose, high
oxygen - Increased intracellular Ca++ external K+
- Astrocytic endfeet envelop endothelial cells
- Astrocytes release TGFα and GDNF that induce tight junctions in vitro
- Aquaporin 4 (AQP4) in pericapillary process
of endfeet - exchange of water & solutes - Astrocytes posses glucose transporters and
other receptors at glial-vascular interface - Neuronal glutamate release, changes in
Ca++ and/or extracellular K+ control capillary
blood flow (dilation or constriction) - Metabotropic glutamate receptors (mGluRs)
- Prostaglandins, NO, arachidonic acid (AA) to regulate blood vessel diameter/flow
- Arachidonic acid (AA) can be converted to;
- PG by COX to initiate vasodilation
- 2-HETE by cytochrome P450 epoxygenase to initiate vasoconstriction
- Metabotropic glutamate receptors (mGluRs) help regulate this
Astrocyte process with pre- and post-synaptic compartments =
tripartite synapse”
astrocytes and gap junctions
Astrocytes Define Functional Domains:
Astrocytes cover specific areas in the brain, creating non-overlapping territories.
Each astrocyte influences all the synapses (connections between neurons) within its territory.
Astrocyte Influence:
Every synapse in an astrocyte’s territory is affected by that single astrocyte.
This means that astrocytes help regulate the activity and function of neurons in their domain.
Syncitial Network:
Astrocytes connect with each other through gap junctions.
These gap junctions allow substances smaller than 1000 kDa (kilodaltons) to pass between astrocytes.
Broad Signal Transmission:
Through their syncitial network, astrocytes can send signals over large areas of the CNS.
They can influence various functions, including blood flow in the brain.
Modulation of Activity:
Astrocytes help modulate brain activity, which can affect mood and other functions.
In summary:
Astrocytes cover specific areas in the brain, influencing all synapses in those areas.
Gap junctions allow communication between astrocytes, affecting large regions of the CNS.
They modulate activity and influence various brain functions, including mood.
Astrocytes and Synapse
Enveloping Synapses:
Astrocytes wrap around synapses in the CNS, providing structural support and regulating synaptic function.
Expression of Neurotransmitter Receptors:
Astrocytes have receptors for most neurotransmitters, allowing them to respond to signals from pre-synaptic neurons.
Activation and Gliotransmitter Release:
Neurotransmitter Release: When neurotransmitters are released from pre-synaptic neurons, they activate receptors on the astrocytes’ processes (perisynaptic glia).
Gliotransmitter Release: Activated astrocytes release gliotransmitters (e.g., glutamate, ATP, D-serine) and increase intracellular calcium ([Ca2+]), which can impact neuronal function elsewhere in the CNS.
Co-Factor Release:
D-Serine: Released by astrocytes to assist in activating NMDA receptors on neurons, which is crucial for synaptic plasticity.
Thrombospondins (TSP1 and TSP2): Promote synaptogenesis (the formation of new synapses), supporting the development and maintenance of synaptic connections.
Synaptic Plasticity:
Astrocytes are essential for synaptic plasticity, the ability of synapses to strengthen or weaken over time, which is important for learning and memory.
Tripartite Synapse
Definition: The tripartite synapse concept involves the interaction between:
Pre-Synaptic Neuron
Post-Synaptic Neuron
Astrocyte Process
Function: This interaction allows for the exchange of information between neurons and astrocytes, facilitating the regulation of synaptic function and plasticity.
Syncitial Network
Network: Astrocytes form a syncitial network through gap junctions, enabling them to communicate and coordinate over large areas of the CNS.
Major Gliotransmitters
Glutamate
ATP
D-Serine
These gliotransmitters play key roles in modulating synaptic activity and overall brain function.
Summary
Astrocytes: Envelop and regulate synapses, express neurotransmitter receptors, release gliotransmitters, and support synaptic plasticity.
Tripartite Synapse: Involves communication between pre-synaptic neurons, post-synaptic neurons, and astrocytes.
Syncitial Network: Astrocytes communicate across large areas via gap junctions.
Gliotransmitters: Key molecules released by astrocytes that influence synaptic function and plasticity.
Glutamate and GABA Metabolism by Astrocytes
Glutamate and GABA Metabolism by Astrocytes
Removal from Synaptic Cleft:
Glutamate: An excitatory neurotransmitter.
GABA: An inhibitory neurotransmitter.
Astrocytes remove these neurotransmitters from the synaptic cleft to regulate their levels and ensure proper neurotransmission.
Metabolism to Glutamine:
After uptake, glutamate and GABA are metabolized within astrocytes to glutamine.
Glutamate is converted to glutamine by the enzyme glutamine synthetase.
GABA is converted to glutamine via an intermediate step involving the enzyme GABA transaminase.
Recycling and Other Uses:
Glutamine can be recycled back to neurons where it is converted into glutamate or GABA, supporting continued neurotransmitter synthesis.
It can also be used in other metabolic processes within the astrocytes.
Plasticity and Excitotoxicity:
Plasticity: Proper regulation of glutamate and GABA is crucial for synaptic plasticity, which involves the strengthening or weakening of synaptic connections and is essential for learning and memory.
Excitotoxicity Prevention: By removing excess glutamate and converting it to glutamine, astrocytes help prevent excitotoxicity (neuronal damage caused by excessive glutamate), protecting neurons from damage.
Summary
Astrocytes remove excess glutamate and GABA from the synaptic cleft.
Glutamate and GABA are converted to glutamine within astrocytes.
Glutamine is recycled to produce neurotransmitters or used in other metabolic activities.
This process supports synaptic plasticity and helps prevent excitotoxicity, maintaining neural health and function.
Potassium Buffering by Astrocytes
Ion Channels in Astrocytes:
Electrophysiological Studies: These studies show that astrocytes have a variety of potassium (K+) and other ion channels.
Increased K+ During Neuronal Activity:
When neurons are active, they release potassium ions into the extracellular space. This increase in K+ concentration needs to be managed to maintain proper neural function.
Spatial Buffering of K+:
Membrane Potential Changes: The increase in extracellular K+ causes a change in the membrane potential of astrocytes. The astrocytic membrane becomes more positive compared to distant membranes.
Current Flow and K+ Influx: This change in potential drives K+ influx into astrocytes.
Syncitial Network: Astrocytes are connected through gap junctions, forming a syncitial network that allows for the spatial buffering of K+ across large areas.
Role of End Feet:
Permeability to K+: Astrocytic end feet, which surround blood vessels, are particularly permeable to K+.
Autoregulation of Blood Flow: K+ release from astrocytes can lead to the dilation of blood vessels, a process known as autoregulation, which adjusts blood flow based on neuronal activity.
Impact on Neuronal Function:
Release of Transmitters: Elevated K+ levels can stimulate astrocytes to release gliotransmitters (e.g., glutamate) that are stored in glial cells.
Impact on Neurons: This release can affect neuronal function and contribute to synaptic plasticity and communication between neurons.
Summary
Astrocytes use various ion channels to buffer excess K+ released during neuronal activity.
Spatial Buffering: Astrocytes redistribute K+ across their network, using their syncitial connections.
End Feet Function: K+ release from astrocytes can dilate blood vessels and influence blood flow.
Transmitters Release: K+ can also trigger the release of neurotransmitters from astrocytes, impacting neuronal activity.
Astrocytes and Synaptic Activity
Metabolism During Neuronal Activity
Peak Activity: When neurons are highly active, astrocytes increase their metabolism.
ADP and Lactate Production: Astrocytes produce ADP (adenosine diphosphate) and lactate during these peak activity periods through non-oxidative metabolism.
Support for Synaptic Activity:
Temporary Sustenance: The lactate and ADP produced can temporarily support both pre-synaptic (neuron releasing neurotransmitters) and post-synaptic (neuron receiving signals) activity.
Energy Supply: This helps maintain the energy needed for continued synaptic function even when demand is high.
Summary
During high neuronal activity, astrocytes produce ADP and lactate.
These products help sustain synaptic activity temporarily by providing additional energy.
Roles of Astrocytes in the Mature CNS
Sheathing and Insulating Unmyelinated Axons:
Astrocytes can envelop and provide insulation to unmyelinated axons, which helps to support their function and maintain their integrity.
Physical Support and Structural Matrix:
Astrocytes provide physical support to neurons and form a structural matrix in the CNS. This support helps maintain the organization and stability of neural tissue.
Nutrient Exchange:
Transporters: Astrocytes have transporters that regulate the exchange of nutrients and other substances between neurons and the blood supply.
Nutrient Delivery: They transport essential nutrients into neurons and remove metabolic waste products.
Regulation of Extracellular Ion Levels and ECS Volume:
Ion Regulation: Astrocytes help regulate extracellular ion levels, particularly potassium (K+), to maintain proper neuronal function.
Control of ECS Volume: They control the volume of the extracellular space (ECS). Significant changes in ECS volume can be problematic (e.g., a 50% decrease in ECS volume can double ion concentrations, which can disrupt neural function).
Expression of Important Molecules:
Growth Factors: Astrocytes produce various growth factors that support neuronal health, development, and repair.
Matrix Molecules and Proteoglycans: They also express matrix molecules and proteoglycans that are crucial for synaptic function, tissue repair, and maintaining the extracellular matrix.
Summary
Sheathing: Insulate unmyelinated axons.
Support: Provide physical and structural support.
Nutrient Exchange: Regulate nutrient and waste exchange.
Ion and ECS Regulation: Control extracellular ion levels and ECS volume.
Molecule Expression: Produce growth factors and matrix molecules essential for normal CNS function.
Microglia Cell Differentiation
Origin:
Peripheral Monocytic Origin: Microglia originate from peripheral monocytic (macrophage) cells.
Entry into CNS: These monocytic cells enter the central nervous system (CNS) from the mononuclear phagocyte populations early in development.
Timing of Events:
Overlap in Development: The timing of regressive events (like cell death) in the CNS overlaps with the migration of macrophages and microglia into the CNS.
Ion Conductance:
Distinct Pattern: Cells destined to become microglia exhibit a different pattern of ion conductance compared to other cells.
Development in the Brain:
Embryonic and Neonatal Distribution: Macrophages are widely distributed in the embryonic and neonatal rat brain.
Morphological Changes: Over time, these cells develop into microglia with complex morphology.
Adult Brain Infiltration:
Low-Level Infiltration: There is continued low-level infiltration of monocytes from the bone marrow into the adult brain.
Relevance to Injury: This infiltration is especially important in response to injury, where monocytes can influence the inflammatory response.
Microglia Phenotypes:
M1 vs. M2: Microglia can adopt different phenotypes, such as M1 (pro-inflammatory) and M2 (anti-inflammatory), depending on the context, particularly in injury and disease.
Markers for Identification:
ED1 (CD68): A marker used to identify microglia and macrophages.
Iba-1: Another marker used to label microglia and monitor their activity and distribution.
Summary
Microglia: Origin from peripheral monocytic cells and enter the CNS early in development.
Development: Show distinct ion conductance patterns and develop complex morphology over time.
Infiltration: Continues into the adult brain, with significant roles in injury and inflammation.
Phenotypes: Can have different roles (M1 vs. M2) based on the state of the CNS.
Markers: ED1 (CD68) and Iba-1 are used to identify and study microglia.
Reactive Gliosis
Activation of Glia:
Astrocytes and Microglia: Reactive gliosis involves the activation of astrocytes and microglia, which respond to pathological changes in the CNS.
Common to Pathological States:
Universality: Reactive gliosis is a response observed in various pathological conditions affecting the CNS, including trauma, disease, and degeneration.
Induction:
Triggers: It can be induced by a range of factors, including:
Substances: Toxic agents or inflammatory molecules.
Trauma: Physical injury to the CNS.
Degenerative Changes: Ongoing neurodegenerative processes.
Scarring:
Scarring: Reactive gliosis often leads to glial scarring, which can impact neuronal function and repair.
Protein and Marker Production:
Pro- and Anti-Inflammatory Proteins: Activated glia produce a variety of proteins and markers that can be pro-inflammatory (promoting inflammation) or anti-inflammatory (reducing inflammation).
Immune Modulation: This production helps modulate the immune response in the CNS, influencing both defense and repair processes.
Role in Defense and Attack:
Central Role: Glial cells are central to both defense mechanisms (protecting against damage and infection) and attack mechanisms (contributing to inflammation and damage in certain conditions).
Summary
Reactive Gliosis: Activation of astrocytes and microglia in response to CNS pathology.
Common Response: Occurs in various pathological states, including trauma and degenerative diseases.
Inducers: Triggered by substances, trauma, and degenerative changes.
Effects: Leads to scarring and the production of inflammatory proteins.
Role: Glial cells play a central role in both defending the CNS and contributing to inflammatory damage.
Reactive Astrocytes
Markers of Activation:
Expression: Reactive astrocytes express various markers upon activation, including:
IL-6 (Interleukin-6)
IL-1Beta (Interleukin-1 Beta)
TNF Alpha (Tumor Necrosis Factor Alpha)
NF’s (Neurofilaments)
NO (Nitric Oxide)
Heterogeneity:
Response Variability: The response of reactive astrocytes to injury can vary based on the type of injury and the surrounding environment.
Environmental Cues:
Influences: Reactive astrocytes respond to various environmental cues, including:
Cytokines: Signaling proteins released by other cells.
Growth Factors: Molecules that promote cell growth and survival.
Adhesion Molecules: Proteins that help cells stick together and communicate.
mTOR: A signaling pathway involved in cell growth and metabolism.
Extracellular Matrix and ECS:
Alterations: Reactive astrocytes can modify the extracellular matrix (ECM) and the structure/volume of the extracellular space (ECS), affecting neural tissue organization and function.
Thrombospondins (TSP1 & TSP2):
Increased Expression: TSP1 and TSP2 levels are increased by reactive astrocytes and activated microglia following focal cerebral ischemia/reperfusion (a type of stroke) in mice (Lin et al., 2003).
Decreased Expression: TSP1 and TSP2 expression can be decreased in some disorders, such as Down Syndrome.
Relevant Literature:
Finsterwald et al. (2015): Discusses astrocytes as new targets for treating neurodegenerative diseases. (Current Pharmaceutical Design)
Jain et al. (2015): Reviews the role of reactive astrogliosis in Alzheimer’s Disease. (CNS Neurological Disorders Drug Targets)
Summary
Reactive Astrocytes: Express various activation markers and respond to multiple environmental cues.
Heterogeneity: Their response to injury varies.
Modifications: Can alter the ECM and ECS structure.
Thrombospondins: TSP1 and TSP2 levels change in response to ischemia and in certain disorders.
Literature: Key studies highlight their roles in neurodegenerative diseases and conditions like Alzheimer’s and Down Syndrome
Astrocytic Regulation of CNS Inflammation
Cytokines and Chemokines:
Function: Astrocytes produce and release cytokines and chemokines that play a key role in regulating inflammation within the CNS.
Chemoattractant Gradients:
Guiding Immune Cells: Astrocytes create gradients of chemoattractants that direct the migration of immune cells into the CNS.
Examples: These gradients guide various immune cells, such as monocytes and other inflammatory cells, to sites of injury or inflammation.
Shaping the Cytokine Milieu:
Influence on Local Environment: Astrocytes shape the local environment by influencing the cytokine and chemokine levels.
Impact on Cells: This influences both recruited immune cells (e.g., monocytes) and resident cells (e.g., oligodendrocytes), affecting their behavior and function.
Outcome of Local Inflammation:
Promotion of Migration: Astrocytic cytokines and chemokines can promote the migration of immune cells to areas of inflammation.
Recruitment of Immunosuppressive Cells: They can also recruit cells that suppress the immune response to help control and resolve inflammation.
Determining Outcomes: The actions of astrocytes ultimately help determine the outcome of local inflammatory responses, influencing whether inflammation resolves or persists.
Summary
Astrocytes regulate CNS inflammation through the production of cytokines and chemokines.
Chemoattractants: Direct the migration of immune cells into the CNS.
Cytokine Milieu: Shapes the local inflammatory environment and influences both recruited and resident cells.
Inflammation Outcomes: Affects the resolution or persistence of inflammation by promoting migration and recruiting immunosuppressive cells.
