Abstract
MicroRNAs (miRNAs) are evolutionarily conserved non-coding RNAs of ∼22 nucleotides that regulate gene expression at the level of translation and play vital roles in hippocampal neuron development, function and plasticity. Here, we performed a systematic and in-depth analysis of miRNA expression profiles in cultured hippocampal neurons during development and after induction of neuronal activity. MiRNA profiling of primary hippocampal cultures was carried out using locked nucleic-acid-based miRNA arrays. The expression of 264 different miRNAs was tested in young neurons, at various developmental stages (stage 2–4) and in mature fully differentiated neurons (stage 5) following the induction of neuronal activity using chemical stimulation protocols. We identified 210 miRNAs in mature hippocampal neurons; the expression of most neuronal miRNAs is low at early stages of development and steadily increases during neuronal differentiation. We found a specific subset of 14 miRNAs with reduced expression at stage 3 and showed that sustained expression of these miRNAs stimulates axonal outgrowth. Expression profiling following induction of neuronal activity demonstrates that 51 miRNAs, including miR-134, miR-146, miR-181, miR-185, miR-191 and miR-200a show altered patterns of expression after NMDA receptor-dependent plasticity, and 31 miRNAs, including miR-107, miR-134, miR-470 and miR-546 were upregulated by homeostatic plasticity protocols. Our results indicate that specific miRNA expression profiles correlate with changes in neuronal development and neuronal activity. Identification and characterization of miRNA targets may further elucidate translational control mechanisms involved in hippocampal development, differentiation and activity-depended processes.
Highlights
The hippocampus is a limbic system structure in the medial temporal lobe of the brain that plays an essential role in learning and memory in animals and humans
In fully differentiated hippocampal neurons, electrophysiological studies have demonstrated the existence of activity-dependent synaptic plasticity such as long term potentiation (LTP) and long-term depression (LTD), which is thought to play a key role in the refinement of neuronal circuitry and considered to be the cellular correlate of learning and memory [1,2,3]
The purpose of this study was to (1) profile miRNAs expressed in primary cultured rat hippocampal neurons, (2) identify specific miRNAs expression patterns during neuronal development, (3) identify miRNAs induced by NMDA receptor-dependent synaptic plasticity and (4) identify miRNAs induced by prolonged changes in global network activity
Summary
The hippocampus is a limbic system structure in the medial temporal lobe of the brain that plays an essential role in learning and memory in animals and humans. Hippocampal pyramidal neurons originate from hippocampal neuroepithelial cells and dentate granular progenitors and undergo typical neurodevelopmental stages involving neuronal polarization, axon outgrowth, dendritogenesis, synapse formation, and maturation of synaptic function. Despite the significance of the hippocampus in forming new memories, our understanding of gene regulation mechanisms that underlie neuronal development and synaptic plasticity is quite limited. Post-transcriptional mechanisms, such as alternative mRNA splicing, mRNA trafficking and translational control are believed to play an important role in the regulation of neuronal gene expression [4,5,6]. It is becoming increasingly clear that the microRNA pathway has an important impact on neuronal development, survival, function, and plasticity [7,8,9]
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