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Flashcards in Astrocytes Deck (17):
1

Introductory info

most numerous glial cell
various functions, depending on brain region or possibly subtype
human astrocytes are larger and more complex than infraprimate mammals, suggesting role has expanded with evolution

2

Synaptic pruning

tag synapses for destruction by microglia phagocytosis (e.g. in dorsal LGN, so that only one or two retinal ganglion cells will synapse onto each cell) via C1q and C3, for binding by C3R on microglia.

Or just phagocytose directly, independent of complement - during metamorphosis, in the drosophila mushroom body, astrocytes release TGFbeta ligand myoglianin to prime neurons for pruning, upregulate cell engulfment molecule Draper (mammalian orthologue is MEGF10) and rearrange cellular morphology to accomodate phagosomes, then phagocytose the axons.

In the developing cerebellum, MEGF10 binds C1q to allow phagocytosis of apoptotic neurons.

3

Synaptic maturation

Astrocytes are the main source of cholesterol in the brain, controlled by SREBPs.

Van Dijk et al 2017 - SREBP Cleavage Activating Protein (SCAP) deletion in the hippocampus decreases presynaptic docked vesicles and SNAP-25 expression

Ferris et al 2017 - Reduced cholesterol synthesis impairs synaptic maturation. Astrocyte specific SREBP2 knockout reduces brain volume and impairs memory in mice

Where synaptic maturation is incomplete, synaptic pruning is blocked - maybe neuronal activity is needed to initiate pruning

4

Formation of excitatory synapses

Various synaptogenic factors inc TGFbeta and TNFalpha
variability in substancers secreted between AND WITHIN brain regions (suggests subpopulations exist)
subpopulations are defined by different cell surface markers like CD51, 63 etc.
Subpopulations allow labelled lines, e.g. hevin needed form thalamocortical but not intracortical synapses in V1.

Ebrahimi et al 2016 - in mouse mPFC, FABP7 is released by astrocytes and OPCs. It has a link with schizophrenia and autism, decreasing prepulse inhibition. KO of FABP7 in vivo and in vitro impairs excitatory synapse formation and decreases dendritic spine density.

some synaptogenic factors can have different effects on different types of neuron, e.g. Glypican 6 increased AMPA expression in retinal ganglion cells, but NMDA expression in hIPS derived neurons

5

Calcium waves

Astrocytes connect in a syncytium, their fibrous processes linked by gap junctions.
Spontaneous calcium oscillations may be driven by GPCRs, but the oscillations are entrained to neuronal activity.
Waves can propagate from process back to soma, (maybe driven by IP3 gradients and spacing between receptors?), or may remain as localised transients. This might depend on subpop of astrocyte (e.g. some may have more densely clustered GPCRs so are more likely to propagate).

Fujii et al 2017 - persistent Ca increases are propagated proximally via gap junctions. Transient Ca increases are propagated slowly by distal extracellular ATP.

Kuga et al 2011 - recording simultaneously from hundreds of mouse hippocampal astrocytes in vivo, found that almost all of them participated in regenerative Ca waves that propagated between cells, termed 'glissandi'. Glissandi were dependent on neuronal activity and accompanied a decreased RBC flow (i.e. they're involved in haemodynamics). Authors suggest that this effect was not seen previously because the astrocytes are so sensitive to light damage.

BUT Fiacco and McCarthy 2004 - uncaging IP3 in an astrocyte causes a robust Ca wave that propagates into the fine processes of that cell, but not to other cells.

6

Neuron-astrocyte communications - basics, and gliotransmitters

Neurons communicate to astrocytes via Gq-coupled GPCRs on the glia which are opened by neurotransmitters etc, and increase Ca conc via mainly the PLC/IP3 pathway. Astrocytes communicate to neurons via gliotransmitters released after this increase in Calcium, which include ATP, D-serine and glutamate.
Gliotransmitters are probably released in a calcium-independent manner, via reversal of glutamate channels, swelling-induced opening of anion channels, connexin hemichannels, and pore-forming purinergic receptors. Calcium-dependent is possible, but has not been reliably demonstrated.

7

Neuron-astrocyte communication - evidence for astrocyte calcium causing glutamate release

Wang et al 2006 - whisker stimulation caused Ca conc increases in astrocytes in the barrel cortex of anaesthetised mice, after 2s in the fine processes and after 3s in the soma. The higher the stimulation frequency, the more astrocytes which responded. Inhibition of mGluR reduced the effect.
Fiacco and McCarthy 2004 - Uncaging IP3 in stratum radiatum astrocytes increased frequency of AMPAR-mediated EPSPs in neighbouring CA1 pyramidal cells. This effect was sensitive to mGluR blockers.

8

Neuron-astrocyte communication - evidence for astrocyte calcium causing ATP release

When the astrocytic Ca increase is caused by SC stimulation, it's ATP that's released (via exocytosis, and converted to adenosine extracellularly), not glutamate. Adenosine acts on presynaptic A1Rs to /decrease/ glutamate release and suppress SC-CA1 synaptic transmission. This may enable LTP, by increasing dynamic range?
Serrano 2006 - stimulating SC cells activated GABA-ergic interneurons, which stimulated GABA receptors on astrocytes, caused Ca increase, ATP release, and suppression of SC-CA1 transmission.

9

Neuron-astrocyte communication - effects of astrocytic calcium increase on neuronal behaviour, or not..!

Perea and Araque 2007 - uncaging Ca in astrocytes elicits glutamate release from Schaffer collateral presynaptic bulbs. When uncaging the Ca was synchronised with postsynaptic depolarisation, the synapse was potentiated.
Fiacco and McCarthy 2004 - Uncaging IP3 in stratum radiatum astrocytes increased frequency of AMPAR-mediated EPSPs in neighbouring CA1 pyramidal cells. This effect was sensitive to mGluR blockers.
Serrano 2006 - stimulating SC cells activated GABA-ergic interneurons, which stimulated GABA receptors on astrocytes, caused Ca increase, ATP release, and suppression of SC-CA1 transmission.

Fiacco et al 2007 - However, stimulating astrocytic Gq GPCRs (either genetically using transgenic MrgA1 receptors, or pharmacologically) increased astrocytic Ca with no effect on frequency of EPSPs.

10

Astrocytes supporting synaptic transmission

Astrocytes ‘ensheath’ synapses - they help terminate transmission by taking up glutamate and turning it into glutamine.
They help facilitate recycling in the neuron too, and take in K (via IR channels?), share that K between them via gap junctions, so that external [K] stays low enough for another AP.
Saab et al 2012 - Inactivation of AMPAR in radial astrocytes (Bergmann glial cells) caused retraction of fine processes and impaired fine motor skills
Han et al 2013 - grafter human glial progenitor cells into mice. Upon maturation, they had gap junction connected to mouse astrocytes, but retained human morphology. Chimaeric mice had enhanced LTP and learning (assessed in mazes and fear conditioning)

11

Lactate shuttle hypothesis

When neurons are more active, they release more glutamate. This is cotransported into the astrocyte with 3Na, which requires ATP. This ATP is produced anaerobically, producing lactate as a byproduct. The lactate is given to the neuron, which can convert it to pyruvate for more energy. It's matching energy supply to demand.
Evidence for - lactate:pyruvate ratio is increased after TBI. Proportion of metabolism accounted for by glucose decreases when there's a sudden perturbation from standard state.
Evidence against - Dienel 2017 - glutamate can be oxidised to 'pay' for its uptake, no need for more glycolysis. Blocking glutamate receptors prevents lactate release but not glutamate uptake. In cultured astrocytes, calculated glycolytic rates and lactate release were not concordant

12

Role of D-serine

Previously thought to be just a gliotransmitter, but now found in neurons too.
As potent an NMDAR coagonist as glycine, to can facilitate excitatory transmission, but also LTP.
Van Horn et al 2017 - acute application of D-serine had no effect on activity, but chronic application increased synaptic maturity and hyperstabilisation of developing axon branches, causing reduced dendritic arbor complexity. But visual fields increased, suggesting reduced synaptic pruning.

Glutamatergic activation causes increased endogenous D-serine, suggesting a feedback loop

13

Astrocytes and cannabinoid receptors

Navarette and Araque 2008 - Astrocytes express CB1 receptors, but Gq linked (as opposed to Gi in neurons, where they mediate retrograde inhibition.) So they cause calcium release, which causes glutamate release, which triggers NMDAR-mediated slow currents in adjacent neurons, which may help synchronise neural networks (think metaplasticity)
Han et al 2012 - Astrocytic but not neuronal CB1 required for LTD at the CA3-CA1 synapse.
Astrocytes can produce endocannabinoids via Ca and ATP-dependent processes, and may contribute to eCB turnover, perhaps interacting with retrograde inhibition.

14

Astrocytes and mental illness

Wildrem et al 2017 - took fibroblasts from schizophrenic children, made iPSCs, then glial cells. Implanted them into mice. Mice became schizophrenic.
Ebrahimi et al 2016 - FABP7 is expressed in astrocytes and OPCs, and has been linked to schizophrenia.

15

Reactive astrocytes

Herrmann et al 2008 - 'Reactive' astrocytes, with different morphology and protein expression, form a glial scar, which was thought to impair regeneration.
This study knocked out the factor allowing astrocytes to become reactive, and found that a glial scar did not form, but in fact the injury looked a bit larger, so maybe reactive astrocytes are protective.

16

Glymphatic system

When you're asleep, AQP4 open in astrocyte foot processes (maybe regulated by pulsatile blood flow), allow fluid that had accumulated in the perivascular aka Virchow-Robin space to flow out into the brain parenchyma, and clear out all the metabolites that accumulated. This is v controversial though.

17

Summary of astrocyte functions

Synaptic pruning
Synaptic maturation
Forming excitatory synapses
Affecting synaptic transmission (via glutamate or adenosine)
Plasticity (LTP with D-serine, metaplasticity via syncytium [Hulme et al 2014])
Lactate shuttle hypothesis
Haemodynamics
Glymphatic system
Maintaining external environment (mopping up K+)