Microglia Function Flashcards
What type of neurodegenerative and developmental disorders can microglia initiate
AD
PD
Autoimmune disease
MS
ASD
Schizophrenia
What is the abundance of microglia in the CNS
5-12%
Features of microglia
Highly motile, extend and retract to monitor environment (tiling)
Large regenerative capacity
Regionally diverse
CNS macrophages
Microglia
Border associated macrophages (BAM)
Development of microglia
Formed during haematopoiesis in the extra embryonic yolk sac
Microglia enter before BBB formation
Microglia cannot be replaced
Microglia turnover rate
8-41 months
Long lived
How can microglia be depleted
Small molecule inhibition
Genetic ablation
Microglia specific genes
Cx3cr1
Tmen119
P2ry12
Sall1
Microglia based therapy
Recovery of healthy functions
Eliminate ‘toxic’ microglia
Cross correction of lost enzymes
Benefit of microglia based therapy
Formed from iPSCs and blood derived substitutes
Microglia replacement reverses ongoing disease progress and prevent progression
Method to study microglia
Single cell technology (Dumas et al., 2021)
What is AAV (adeno-associated virus)
Do not activate microglia
Cloned with cas9/sgRNA to knock down genes only in microglia
Cre ER/loxP system allows time dependent in/activation
Why are AAV capsid proteins used
Traditional AAVs for gene therapy target neurons not microglia
Direct evolution forms AAV capsids (viral protein shell) which target microglia
Variants: AAV-cMG and AAV-MG deliver genes to microglia
What determines microglia density and molecular state
Pyramidal neurons (somatosensory cortex)
Main functions of embryonic and post natal microglia
Cell death and apoptosis (NGF/ROS/TNF)
Axon outgrowth and fasciculation (f: glutamatergic axons) (o: dopaminergic axons)
Cortical interneuron migration
Neuronal cell survival and oligodendrocytes
Synaptic spine formation and presynaptic pruning
how do astrocytes and microglia optimise function (synapse formation and neuronal signalling)
microglia are ramified
surveilence motility
secretory
P2Y12high
how do astrocytes and microglia optimise survival (physical barrier and engulf pathogen)
microglia are ameboid
highly phagocytic
directionally chemotactic
P2Y12low
old view vs new view
old: rigid, dichromatic organisation
new: coexistence of multiple states
when do microglia induce synapse formation
P8-10
schafer et al., 2012
microglia prune synapses during circuit refinement
‘eat’ weak presynaptic terminals
more active synapses less likely to be targeted by microglia
complement system needed for microglial pruning (CR3)
how do microglia influence connectivity in the visual system
immature with overlapping projections then mature with separate projections
in dLGN
complement activation
start: expression and activation of C1q
major convergence at C3
C3 cleavage into opsonin (C3b and C3a)
opsonisation with C3b causes elimination of target structure by phagocytes
how do microglia refine retinogeniculate projections
-competition between strong and weak synapses
-complement upregulated in RGCs by astrocyte signalling
-local activation of complement system causes deposition of C3b on weaker synapses (eat me) phagocytes by microglia expression C3 receptor
-C3b and CD47 is a dont eat me signal for stronger synapses
what is the punishment model of synaptic stabilisation
weaker synapses fail to establish a protective molecular signal
microglia engulf via phagocytosis
how do microglia promote synaptic formation
actin accumulation precedes filopodia formation
how do microglia control neural circuits involved in sex specific behaviours
brain masculisation
epigenetic supression in brain feminisation
how does sexual identity influence microglia development
males and females have distinct transcriptomic signature of microglia
sex differences in psychiatric disorders
ASD 4-5x higher in males
ADHD 2-3x higher in males
early life programming of sex differences
activation of sex specific circuits for mating
modulation of social and emotional behaviour
changes in cognitive learning strategies
rodent critical window
onset of gonadal steroid production in males during birth
no steroidogenesis in females
expression of chromatin modifying enzymes and DNA methylases
how do males have social play
adolescent social play correlates to D1r expression
D1r receptor removed by microglia in males (less social play)
if C3+ D1r synapses and C3R+ receptor microglia abolished (social play is maintained)
how does negative feedback occur via microglia
Badimon et al., 2020
ATP released by active synapses and associated with astrocytes
ATP converted to AMP then adenosine (ADO) by microglia
ADO suppresses pre and post synaptic neuronal excitability by reducing cAMP cia A1r receptor
what do inhibitory interneurons and microglia inhibit
active neurons
role of GABA receptive microglia prune inhibitory synapses
engulf inhibitory synapses
different behavioural changes in female and less engulfment in male GABA B2 receptor KO
how do microglia enable plasticity
microglia endowed with IL-33 receptor upregulates/secretes enzymes degrading ECM
