MicroRNA-34a Acutely Regulates Synaptic Efficacy in the Adult Dentate Gyrus In Vivo

Abstract

Activity-dependent synaptic plasticity involves rapid regulation of neuronal protein synthesis on a timescale of minutes. miRNA function in synaptic plasticity and memory formation has been elucidated by stable experimental manipulation of miRNA expression and activity using transgenic approaches and viral vectors. However, the impact of rapid miRNA modulation on synaptic efficacy is unknown. Here, we examined the effect of acute (12 min), intrahippocampal infusion of a miR-34a antagonist (antimiR) on medial perforant path-evoked synaptic transmission in the dentate gyrus of adult anesthetised rats. AntimiR-34a infusion acutely depressed medial perforant path-evoked field excitatory post-synaptic potentials (fEPSPs). The fEPSP decrease was detected within 9 min of infusion, lasted for hours, and was associated with knockdown of antimir-34a levels. Antimir-34ainduced synaptic depression was sequence-specific; no changes were elicited by infusion of scrambled or mismatch control. The rapid modulation suggests that a target, or set of targets, is regulated by miR-34a. Western blot analysis of dentate gyrus lysates revealed enhanced expression of Arc, a known miR-34a target, and four novel predicted targets (Ctip2, PKI-1α, TCF4 and Ube2g1). Remarkably, antimiR-34a had no effect when infused during the maintenance phase of long-term potentiation. We conclude that miR-34a regulates basal synaptic efficacy in the adult dentate gyrus in vivo. To our knowledge, these in vivo findings are the first to demonstrate acute (< 9 min) regulation of synaptic efficacy in the adult brain by a miRNA.

Arc/Arg3.1 function in long‐term synaptic plasticity: Emerging mechanisms and unresolved issues

“…Arc is a target of the microRNA, miR34a (Wibrand et al., 2012). Local intrahippocampal infusion of a miR34a‐inhibitor (Berentsen et al, 2019) induced upregulation of Arc and several other bioinformatically predicted miR34a targets. The depression of synaptic transmission started within 10 min of infusion and was nucleotide sequence‐specific, as scrambled and mismatch antagomirs did not affect miR34a target expression or synaptic efficacy.…”

Cell-to-Cell Communication in Learning and Memory: From Neuro- and Glio-Transmission to Information Exchange Mediated by Extracellular Vesicles

“…miR-9-derived miR-9-3p [226] Dystrophin [226]; Voltage-dependent Calcium channel, g subunit [226,227]; Leucine rich repeat transmembrane neuronal 1 [226,228]; Cadherin 2 [226,229]; Fibronectin [230]; Calcineurin B, type I [226,231] Regulates synaptic plasticity and memory [226] Found in serum exosomes of acute ischemic stroke patients [217] miR-17-92 cluster: miR-17, miR-18a, miR-19a, miR-19b, miR-20a, and miR-92a [213,[232][233][234] Phosphatase and Tensin Homolog (PTEN) [211,234] -Regulate axonal outgrowth in development [211]; -Regulate adult hippocampal neurogenesis, anxiety, and depression [232]; -Enhance neuroplasticity and functional recovery after stroke [233,234]; -Enhance neurite remodeling, neurogenesis and angiogenesis in post-stroke rats [233]; -Ablation in mouse impairs hippocampal-dependent learning and memory [212] miR-19a found in exosomes [213,233] miR-26a [209] PTEN, GSK-3, BDNF [209] Stimulates neurite/axonal elongation [209] Found in astrocytic exosomes [209] miR-29c [235] Beta secretase 1 (BACE1) [236] This microRNA can be an endogenous regulator of the BACE 1 enzyme, and thus of beta amyloid precursor protein (APP) metabolism. [236] Found in exosomes contained in frozen post-mortem prefrontal cortex from bipolar individuals [235] miR-34a [237] Activity-regulated cytoskeleton-associated protein (Arc) Chicken ovalbumin upstream promoter transcription fa...…”

Microglial Morphology Across Distantly Related Species: Phylogenetic, Environmental and Age Influences on Microglia Reactivity and Surveillance States

“…In fact, the generation of LTP through the N-methyl-D-aspartate receptor (NMDAR) activates transcription factors that promote the expression of genes responsible for its maintenance (82). Indeed, it has been demonstrated that through enhanced expression of the Arc gene, a key regulator of synaptic plasticity, miR-34a regulates basal synaptic efficacy in the adult medial perforant path-evoked synaptic transmission in the DG (83).…”