miRNA systems in synaptic plasticity
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How are miRNAs synthesised?
RNA Pol II → pri-miRNA → Drosha/DGCR8 → pre-miRNA → Exportin-5 → Dicer/TRBP → miRNA duplex → Ago loads guide strand → RISC.
Where does Drosha act and what does it generate?
In the nucleus; cleaves pri-miRNA to produce pre-miRNA hairpin.
How does Exportin-5 function?
Binds pre-miRNA with Ran-GTP and transports to cytoplasm.
What is Dicer’s role?
Cleaves pre-miRNA loop in cytoplasm, producing ~22 nt duplex and loads guide strand into Ago.
What defines target specificity?
Seed region (nt 2–8) base-pairs with complementary sites in mRNA 3’UTRs.
How does RISC silence gene expression?
RISC recruits GW182 → CCR4-NOT/PAN2-PAN3 for deadenylation → DCP1/2 for decapping → XRN1 for degradation.
What is Ago2 slicing?
Perfect complementarity leads to endonucleolytic mRNA cleavage by Ago2 (rare in mammals).
Why are miRNAs perfect for dendritic regulation?
They hold mRNAs in a ready-but-silent state, enabling rapid, synapse-specific protein synthesis.
What proteins allow local processing at spines?
Dicer and TRBP are present at dendrites and spines.
How fast can miRNA-mediated changes occur?
Seconds–minutes for local processing/translation; hours–days for transcription and consolidation.
What does miR-134 repress?
Limk1 translation in dendrites.
What is the basal state of miR-134?
Limk1 low → cofilin active → actin severing → small spines.
How does activity relieve miR-134 repression?
BDNF → TrkB → PI3K/mTOR → Limk1 translation → cofilin phosphorylation → spine enlargement.
Why is miR-134 called the textbook example?
Direct link: miRNA → local translation → actin → spine morphology during structural LTP.
How is miR-132 induced?
NMDAR → Ca²⁺ → CaMK → CREB → miR-132 transcription.
Primary target of miR-132?
p250GAP (which inhibits Rac1).
Downstream effect of miR-132?
p250GAP ↓ → Rac1 ↑ → Arp2/3 → actin polymerisation → spine growth and synaptic strengthening.
Behavioural relevance of miR-132?
Required for experience-dependent plasticity, learning, memory.
What does miR-138 target?
APT1 (acyl protein thioesterase).
Mechanistic outcome of miR-138?
APT1 ↓ → Gα12/13 palmitoylation → RhoA activation → actin stabilisation → spine shrinkage.
Which miRNAs control NMDAR-LTD?
miR-191 ↓ and miR-135 ↑.
Targets of miR-191 and miR-135?
miR-191: Tropomodulin-2; miR-135: Complexin-1/2.
Functional outcome of miR-191/135?
Both required for spine shrinkage and LTD; blocking either prevents LTD.
How does neuronal activity change miRNA function?
Transcriptional induction, local Dicer processing, RISC composition, alternative 3’UTRs, exosomal transfer.