Glia 2

Why are astrocytes generated before oligodendroglia?

Astrocytes are needed early to establish and organise the CNS environment.

How long can oligodendrocyte maturation and myelination continue in humans?

Into the twenties, with different white-matter regions maturing at different rates.

What general principle describes astrocyte diversity?

How diverse can astrocyte subpopulations be?

Morphology, molecular profile, and function vary with CNS region, developmental stage, and physiological or pathological state.

They can differ from one another as strongly as they differ from neurons.

Where are radial astrocytes found?

Where are protoplasmic astrocytes found?

Where are fibrous astrocytes found?

What are Bergmann glia and where are they found?

Where are velate astrocytes found?

Where are interlaminar astrocytes found?

Around ventricles, retaining elongated radial organisation.

Grey matter, where highly branched processes surround synapses.

White matter, associated with axon tracts.

Specialised radial astroglia in the cerebellum.

In the cerebellar granule-cell layer.

In supragranular layers of the cerebral cortex.

How do striatal astrocytes affect dopaminergic neurons?

How do mesencephalic astrocytes affect dopaminergic neurons?

They favour elongated axonal processes.

They favour greater branching.

What happens when neurons are cultured with or without astrocytes?

Without glia, retinal ganglion cells and cerebellar neurons form fewer, poorly functioning synapses. Adding astrocytes:

• increases synapse number

• increases the frequency and size of miniature EPSCs

• reduces failures during evoked synaptic transmission

How do astrocytes organise and refine synapses?

Astrocytes provide local molecular and structural cues that control where synapses form and mature. They regulate postsynaptic dendritic spines and work with microglia to recognise and remove inappropriate synapses during pruning.

What is the blood–brain barrier and what forms it?

Diffusion barrier controlling influx of molecules based on polarity and size but allows oxygen and hormones which can influence activity.

formed by tight junctions between capillary endothelial cells

How do astrocytes support the BBB?

Astrocyte endfeet wrap around capillaries and release factors such as TGFα and GDNF, which help induce and maintain endothelial tight junctions. The astrocytes support the barrier, but the endothelial cells physically form it.

What is the role of AQP4 in perivascular endfeet?

What is the role of glucose transporters at the glial–vascular interface?

It regulates water and solute exchange.

They help supply metabolically active neural tissue.

What is neurovascular coupling?

Matching local blood flow, oxygen, and nutrient delivery to neuronal activity.

What 3 molecules regulate blood vessel diamater/flow?

Prostaglandins, nitric oxide, AA arachidonic acid

How do astrocytes match blood flow to neuronal activity?

• High neuronal activity increases glutamate release from presynaptic terminal

• Astrocyte takes up glutamate which increases? extracellular K⁺.

• Astrocytes detect these signals, increasing their intracellular Ca²⁺.

• This activates arachidonic acid (AA) pathways that control blood-vessel diameter:

  • AA → COX (cyclo-oxygenase)→ prostaglandins → vasodilation, increasing blood flow, oxygen and glucose delivery.

  • AA → cytochrome P450 → 2-HETE(hydroxyeicosatetraenois)-related products → vasoconstriction, reducing local blood flow.

• The final response depends on local signalling and metabolic conditions, allowing blood supply to match neuronal demand.

What is an astrocytic domain and why are they important?

How are neighbouring astrocytes connected?

A largely non-overlapping territory occupied by one astrocyte. One astrocyte can influence many or all synapses within its territory. its processes interact with neurons while its end feet contact blood vessels which allows it to control the local environment.

By connexin-based gap junctions.

What is an astrocytic syncytium?

A functional network of astrocytes connected by connexin based gap junctions.

How does the syncytium support spatial K⁺ buffering?

K⁺ taken up in a high-concentration region can be redistributed through connected astrocytes to lower-concentration or perivascular regions.

How can a local synaptic event influence a wider circuit through astrocytes?

Astrocytic networks redistribute ions, metabolites, and signals across multiple domains.

What is a tripartite synapse?

• It has three parts:

  • Presynaptic terminal

  • Postsynaptic compartment

  • Surrounding astrocytic process

• It is called tripartite because astrocytes actively sense and modify communication between the two neurons.

How does tripartite signalling occur?

• Presynaptic neurotransmitter release activates the perisynaptic astrocyte.

• Astrocytic Ca²⁺ rises, altering transmitter uptake or triggering release of gliotransmitters like glutamate, ATP or D-serine.

• D-serine helps activate NMDA receptors (It’s a co agonist of NMDA).

• This modifies synaptic activity and plasticity.

What do thrombospondins TSP1 and TSP2 do?

They promote synaptogenesis.

How do astrocytes regulate synaptic plasticity?

They detect activity, control transmitter and ion levels, release modulatory signals, provide metabolic support, and organise synapse formation and removal.

Why do astrocytes remove glutamate and GABA from the synaptic cleft?

Which astrocyte-encriched transporters remove glutamate?

To terminate signalling, prevent accumulation, and support repeated neurotransmission.

GLT-1 and GLAST specifically remove glutamate; GABA uses separate GABA transporters.

What happens to glutamate and GABA carbon skeletons in astrocytes?

What happens to the end product?

They are converted into glutamine by glutamine synthetase and glutamine is returned to neurons for neurotransmitter resynthesis or used for other pathways

How does the cycle support synaptic plasticity?

It replenishes neurotransmitter precursor while keeping extracellular transmitter within safe limits.

Why does extracellular K⁺ rise during neuronal activity?

How do astrocytes respond to local K⁺ accumulation?

Action potentials and synaptic activity move K⁺ out of neurons.

Their abundant K⁺ channels take it up.

What is spatial potassium buffering and why is it important?

Astrocytes take up K⁺ where it is high causing astrocyte to be more positive causing potential difference that driver current so K+ and redistribute it through the syncytium toward lower-concentration regions and perivascular endfeet. It prevents sustained neuronal depolarisation and uncontrolled excitability.

How can perivascular K⁺ release affect vessels?

It changes vessel diameter and contributes to regulating blood flow

What other extracellular variables do astrocytes regulate?

Water, pH, nutrients, extracellular volume, and numerous ions.

How do astrocytes support synaptic activity during high energy demand?

• During intense neuronal activity, ATP is used and ADP rises.

• Astrocytes use non-oxidative glucose metabolism to produce lactate.

• Lactate is supplied to neurons as a temporary energy source.

• This helps sustain both pre- and postsynaptic activity.

How do HSCs produce tissue macrophages?

• HSC → common myeloid progenitor → myeloblast → promonocyte → monocyte

• Monocytes circulate in the blood.

• After entering tissues and mucosa, they can differentiate into unpolarised M0 macrophages.

• Local signals then push M0 macrophages towards different functional states.

Are microglia normally replaced continuously by circulating monocytes?

No. They form a long-lived, self-renewing CNS population.

What are M1 and M2 macrophage states?

• M1: mainly pro-inflammatory and helps destroy pathogens.

• M2: mainly involved in reducing inflammation, tissue repair and remodelling.

• M2 includes several subtypes: M2a, M2b, M2c and M2d.

Where do microglia come from?

their lieneage, when their progenitor arise in mic and when they enter the developing brain and what they form

• Microglia belong to the myeloid lineage.

• In mice, their progenitors arise in the yolk sac around E7.5–E8.5.

• They enter the developing brain before the BBB forms, around E9.5–E10.5.

• They then form a long-lived population that self-renews inside the CNS rather than being continually replaced by circulating monocytes.

What are the two main brain-macrophage populations?

• Microglia: live within the brain parenchyma.

• Border-associated macrophages (BAMs): live in meninges, perivascular spaces and other CNS-border regions.

• Their different environments give them distinct phenotypes and epigenetic identities

Which signals control microglial development and survival?

• TGF-β signalling: required for microglial differentiation and identity.

• CSF1–CSF1R signalling: supports microglial survival, maintenance and function.

What do Iba1 and CD68/ED1 indicate?

• Iba1: a broad intracellular marker of microglia and macrophages.

• CD68/ED1: mainly a lysosomal marker; increased expression suggests greater phagocytic or phagolysosomal activity.

How do resting/surveillant microglia monitor the CNS?

Their motile processes continuously sample the local environment.

What is the neuronal fractalkine ligand and what is the corresponding microglial receptor?

what does it do

CX3CL1. receptor: CX3CR1.

involved in bidirectional signaling that allows the microglia to maintain the health of a healthy neurons and respond appropriately if the neuron is damaged

What is reactive gliosis?

How does reactive astrocyte morphology change and what activates them?

Coordinated activation of astrocytes and microglia during CNS pathology, trauma, or degeneration.

Astrocytes become hypertrophic. Activated by cytokines, GF, adhesion signals etc

Is reactive gliosis intrinsically beneficial or harmful?

No. Early responses can contain damage and clear debris, while prolonged activation can disrupt homeostasis and inhibit repair.

Which inflammatory mediators can reactive astrocytes express?

IL-6, IL-1β, TNF-α, and nitric-oxide-related pathways.

How do reactive astrocytes change the tissue environment?

How do astrocytic cytokine and chemokine gradients affect other cells?

They modify extracellular matrix and extracellular-space volume.

They recruit immune cells and shape monocyte, oligodendrocyte, and microglial behaviour.

How can TSP1/2 change after injury and in some disorders

TSp1 and 2 increased in reactive astrocytes and activated microglia after injury and they can be decreased in some disorder eg down syndrome

What do reactive microglia do at lesions?

How can microglia alter astrocyte phenotype?

Migrate, proliferate, clear necrotic material and damaged synapses/neurons, and release inflammatory or repair mediators.

Microglial signals can induce neurotoxic A1-like astrocyte states.

How do microglia use TREM2 in synaptic pruning?

TREM2 helps microglia recognise and engulf weak or unwanted synapses during development, refining neural circuits.

What is a glial scar, and how can it be both helpful and harmful?

• Contains reactive astrocytes, microglia, meningeal cells, OPCs and sometimes fibroblasts.

• Early: protects healthy tissue by containing inflammation, dead cells and toxins.

• Later: forms physical and chemical barriers that restrict axon regrowth

How do CSPGs Chondroitin-sulfate proteoglycans (CSPGs). and chondroitinase affect axon regeneration?

• Scar tissue contains high levels of CSPGs, which inhibit axon growth.

• Chondroitinase breaks down CSPGs and can improve axon growth and recovery.

• Treatment needs on/off control because excessive CSPG removal could disrupt healthy circuits.

What is the goal of glial-scar treatment?

• Preserve the scar’s early protection and astrocytic support.

• Reduce its long-term inhibition of axon growth.

• NeuroD1 may reprogramme some reactive astrocytes into neurons, but converting too many could remove essential containment and support.

How does ageing affect the extracellular and glial environment?

• Alters extracellular space, proteoglycans and diffusion.

• Disorganises astrocytic processes and can cause gliosis.

• Disrupted diffusion may affect sleep, memory and local signalling and contribute to chronic pain, depression and cognitive impairment.

What may contribute to cognitive ageing?

• Learning-impaired aged rats show altered hippocampal proteoglycans, impaired diffusion and disorganised glial processes.

• Cognitive decline may result from a loss of glial homeostatic support, not just increased inflammation.