Abstract
The SNARE-mediated vesicular transport pathway plays major roles in synaptic remodeling associated with formation of long-term memories, but the mechanisms that regulate this pathway during memory acquisition are not fully understood. Here we identify miRNAs that are up-regulated in the rodent hippocampus upon contextual fear-conditioning and identify the vesicular transport and synaptogenesis pathways as the major targets of the fear-induced miRNAs. We demonstrate that miR-153, a member of this group, inhibits the expression of key components of the vesicular transport machinery, and down-regulates Glutamate receptor A1 trafficking and neurotransmitter release. MiR-153 expression is specifically induced during LTP induction in hippocampal slices and its knockdown in the hippocampus of adult mice results in enhanced fear memory. Our results suggest that miR-153, and possibly other fear-induced miRNAs, act as components of a negative feedback loop that blocks neuronal hyperactivity at least partly through the inhibition of the vesicular transport pathway.
Highlights
It is widely believed that the formation of stable memories involves changes in the strength of synaptic connections between neurons that are activated during learning (Greer and Greenberg, 2008; Kandel, 2001; Lynch, 2004)
Further analysis of the 15 genes identified in this pathway revealed binding 146 sites for 12 of the 21 miRNAs (Supplementary file 1B). These findings suggest that this group of miRNAs may be part of a regulatory network involved in suppressing vesicle exocytosis, a process that is required for neurotransmitter release, insertion of receptors at the synapse, and memory formation
To assess whether the expression of miR-153 215 is induced during the maintenance of long term potentiation (LTP), we examined perforant path-dentate gyrus LTP (PP216 DG LTP) in acute hippocampal slices prepared from adult mice (Figure 3B)
Summary
It is widely believed that the formation of stable memories involves changes in the strength of synaptic connections between neurons that are activated during learning (Greer and Greenberg, 2008; Kandel, 2001; Lynch, 2004). Sensory experience results in altered neurotransmitter release at the synapse, which triggers membrane depolarization and calcium influx into individual neurons. This action initiates a cascade of downstream events including the activation of protein kinases, redistribution of neurotransmitter receptors, and induction of changes in gene expression, which together lead to stable changes in synaptic strength (Flavell and Greenberg, 2008; Malinow and Malenka, 2002; Sutton and Schuman, 2006). Hundreds of miRNAs have been identified in mammalian genomes (Bartel, 2004; Lewis et al, 2003), many of which are expressed in neurons
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