Mol. Cells 2014; 37(7): 511-517
Published online June 24, 2014
https://doi.org/10.14348/molcells.2014.0132
© The Korean Society for Molecular and Cellular Biology
Correspondence to : *Correspondence: kaang@snu.ac.kr
MicroRNAs are non-coding short (~23 nucleotides) RNAs that mediate post-transcriptional regulation through sequence-specific gene silencing. The role of miRNAs in neuronal development, synapse formation and synaptic plasticity has been highlighted. However, the role of neuronal activity on miRNA regulation has been less focused. Neuronal activity-dependent regulation of miRNA may fine-tune gene expression in response to synaptic plasticity and memory formation. Here, we provide an overview of miRNA regulation by neuronal activity including high-throughput screening studies. We also discuss the possible molecular mechanisms of activity-dependent induction and turnover of miRNAs.
Keywords high-throughput screening, miRNA induction, miRNA turnover, neuronal activity, NMDAR
Neuronal activity induces various cellular and molecular changes, which results in the alteration of synaptic strength. In particular, at the synapse level, each synapse shows dynamic responses to specific neuronal activity within a few minutes, which implies that fast and precise molecular machineries are indispensable (Lee et al., 2009; Matsuzaki et al., 2004; Padamsey and Emptage, 2011).
Recent studies revealed a novel post-transcriptional regulatory system using small non-coding RNAs, so-called microRNAs (miRNA), which inhibit protein synthesis by imperfect complementary binding to 3′ untranslated region (3′UTR) of target mRNAs. Transcription of miRNAs produces long primary miRNAs (pri-miRNAs), and then these are processed by Drosha to precursor miRNAs (pre-miRNAs) which form a single hairpin structure. These pre-miRNAs are exported to the cytoplasm by Exportin 5 and further processed by Dicer to ~23-nucleotide-long mature miRNAs. Mature miRNAs are loaded into the RNA-induced silencing complex (RISC) and bind to 3′UTR of target mRNAs, which results in translational repression and/or mRNA destabilization (Bartel, 2004; Im and Kenny, 2012; Xiong et al., 2013). Translational repression of mRNA driven by miRNAs is an attractive regulatory system for explaining rapid local protein synthesis in response to neuronal activity (Huber et al., 2000; Martin et al., 1997; Sutton and Schuman, 2006). The evidence from many studies showing some miRNAs are specifically enriched in dendrites and synaptosomes also implies the role of miRNAs in neuronal activity (Kye et al., 2007; Lugli et al., 2008; Schratt et al., 2006; Siegel et al., 2009).
In this review, we summarize recent studies reporting activity-dependent regulation of miRNAs and discuss how miRNAs are regulated by various types of neuronal activity.
Numerous studies have shown that miRNAs are critically regulated by neuronal activity. We summarized a decade of research showing direct regulation of miRNAs in response to various types of neuronal activity (Table 1).
The first and most studied miRNA induced by neuronal activity is miR-132. Many studies have shown a consistent increase of miR-132 after various types of neuronal activity such as brain-derived neurotrophic factor (BDNF), KCl (membrane depolarization) and bicuculline (GABAR Receptor inhibition) in cultured neurons (Chai et al., 2013; Klein et al., 2007; Vo et al., 2005; Wayman et al., 2008) and seizure, contextual fear conditioning, odorant stimulus, light, cocaine intake and visual stimulus in particular brain regions of living animals (Cheng et al., 2007; Im et al., 2010; Nudelman et al., 2010; Tognini et al., 2011). Moreover, reduced neuronal activity such as monocular deprivation in visual cortex decreases both pre- and mature miR-132, strengthening the evidence for neuronal activity-dependent miR-132 induction (Mellios et al., 2011; Tognini et al., 2011). The induction of miR-132 is regulated by cAMP response element binding protein (CREB) which is a crucial stimulus-induced transcription factor regulating many fast-response genes and playing a key role in dendritic development and synaptic plasticity. Studies using pharmacological inhibitors showed that the induction of miR-132 requires activation of NMDA receptor, CaM kinase and MEK-ERK pathways (Cheng et al., 2007; Wayman et al., 2008).
miR-212 is another CREB-dependent miRNA. The locus of miR-212 is located only 200 bases upstream from that of miR-132 and the promoter regions of both miR-132 and miR-212 have CRE sequences (Magill et al., 2010; Remenyi et al., 2013; Vo et al., 2005). There are fewer studies about miR-212 compared to miR-132. Kenny and colleagues have studied the role of miR-212 in cocaine addiction related to CREB signaling in dorsal striatum (Hollander et al., 2010; Im et al., 2010). Authors showed that miR-212 is specifically induced by extended but not restricted cocaine access and amplifying CREB signaling
The regulation of miR-134 is more complicated than other miRNAs. Schratt et al. (2006) showed that synaptodendritically localized miR-134 negatively regulates dendritic spine size by repressing the translation of target Lim-domain-containing protein kinase 1 (LimK1) mRNA. After BDNF treatment, the translation of LimK1 is increased by the relief of miR-134 inhibition, which suggests miR-134-associated silencing complex is inactivated or diminished at the synaptodendritic compartment. On the other hand, Fiore et al. showed that BDNF stimulation increases the level of pre-miR-134
The brain-enriched and highly conserved miRNA miR-124 has been studied largely for its role in neuronal development (Cao et al., 2007; Cheng et al 2009; Landgraf et al 2007; Makeyev et al., 2007; Yu et al 2008). Kandel and colleagues first demonstrated the activity-dependent regulation of miR-124 in
The study of Krol et al. (2010) provides clear evidence of dynamic regulation of miRNAs by a stimulus. Several retinal miRNAs, miR-183/96/182 cluster, miR-204 and miR-211, were dynamically up- and down-regulated by light. The levels of these miRNAs were remarkably decreased by dark adaptation and rapidly recover to their maximum levels within 30 min after return to light.
There are several screening studies looking for global changes of miRNAs after neuronal activities (Table 2).
The study of Park and Tang examined a time-dependent change in miRNAs after chemical LTP (c-LTP) or metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) in hippocampal slices. Among 237 miRNAs tested by microarray, 50 miRNAs and 59 miRNAs were increased more than 8 folds after c-LTP and mGluR-LTD stimulation, respectively. Interestingly, most of the miRNAs were increased within 15 min after c-LTP and 30 min after mGluR-LTD (Park and Tang, 2009).
The rapid induction of miRNAs was also observed in living animals. Electroconvulsive shock was given to induce massive and synchronous depolarization of hippocampal neurons. Expression levels of miRNAs measured by Taqman low-density array showed that most miRNAs were increased rapidly within 1 h (Eacker et al., 2011).
Bramham and colleagues performed microarray analysis using the high frequency stimulus (HFS) paradigm for
The study of van Spronsen et al. (2013) examined the activity-dependent change in miRNA using mature primary hippocampal neuron cultures. The authors investigated the change in 264 miRNAs after NMDA receptor-mediated synaptic plasticity or homeostatic synaptic plasticity using microarray analysis. A chemical LTP or a chemical long-term depression (LTD) protocol was used for NMDA receptor-mediated synaptic plasticity, which induced a change in expression of 51 miRNAs. For homeostatic synaptic plasticity, either voltage-gated sodium channel blocker tetrodotoxin (TTX, suppress action potential) or GABAA receptor antagonist bicuculline (increase synaptic activity) was treated for 4 h or 48 h. Prolonged change of synaptic activity in neuron culture altered the expression of 31 miRNAs.
Specific experiences may induce the changes in miRNA expression. Kye et al. (2011) studied the change in miRNAs in the hippocampus after contextual fear conditioning. The expression of 187 miRNAs in the hippocampal CA1 region was measured by quantitative real time PCR (qRT-PCR) at three different time points after training (1 h, 3 h, and 24 h). Astonishingly, a single training session significantly changed the expression level of almost half of measured miRNAs (90 miRNAs). Sur and colleagues screened miRNAs in the primary visual cortex (V1) responding to visual deprivation
Interestingly, there is a report showing that miRNA dysregulation is linked to the pathogenesis of neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) (Campos-Melo et al., 2013). This study analyzed the expression profile of 664 miRNAs in the sporadic ALS spinal cord tissues. The results showed that there is a specific group of dysregulated miRNAs and that specific miRNA dysregulation might be related to the selective suppression of neurofilament miRNA observed in sporadic ALS.
There are two possible mechanisms for the induction of miRNA (Fig. 1). The first mechanism is suggested by the finding which showed neuronal activity induces the cleavage of Dicer and increases its RNAse III activity. This study showed that enzymatically inactive Dicer is enriched at postsynaptic densities (PSD), and is released and activated by calcium-dependent calpain activation (Lugli et al., 2005). Because Dicer is a key enzyme to produce mature miRNAs, the release of active Dicer might process most of the pre-miRNAs located in dendritic spine all at once. This mechanism may explain the results of previous studies reporting fast induction of many miRNAs after stimulation (Eacker et al., 2011; Park and Tang, 2009). The second miRNA induction mechanism is
Compared to induction of miRNA, little is known of the activity-dependent neuronal miRNA turnover. This lack of attention might be related to previous studies which have shown that miRNAs are highly stable and have slow turnover rates (Bhattacharyya et al., 2006; Gantier et al., 2011; van Rooij et al., 2007). Meanwhile, Krol et al. (2010) provide a new insight into the nature of miRNA turnover, reporting that miRNAs in neuron have rapid turnover rates that are dependent on neuronal activity. The level of miRNAs in mouse retina was rapidly, within a few hours, decreased after transcriptional shut-down
Until now, almost nothing is known about the mechanism for neuronal activity-dependent miRNA turnover. One possible mechanism is the degradation of RISC by neuronal activity (Fig. 1). In
Synaptic activity across neurons is the most fundamental feature of neurons. We focused here on how neuronal activity regulates the level of miRNAs. From a decade of efforts, a good body of evidence has elucidated the mechanism of miRNA regulation. Particularly, high-throughput studies provide new insights for understanding global changes in miRNAs.
In the future, more studies about cell type-specific or neuronal circuit-specific miRNA regulation are demanded to understand the diversity and complexity of brain function.
. Neuronal activity-dependent regulation of microRNAs
miRNA | Neuronal sources | Stimuli to induce neuronal activity | Regulation of miRNAs | References | ||
---|---|---|---|---|---|---|
Primary | Precursor | Mature | ||||
let-7d | Ventral tegmental area | Cocaine | Chandrasekar and Dreyer (2009) | |||
miR-96 | Retina | Dark adaptation | Krol et al. (2010) | |||
miR-124 | Aplysia neurons | Serotonin | Rajasethupathy et al. (2009) | |||
Caudate putamen | Cocaine | Chandrasekar and Dreyer (2009) | ||||
Ventral tegmental area | ||||||
miR-128b | Infralimbic prefrontal cortex | Fear extinction learning | Lin et al. (2011) | |||
miR-132 | Cortical neuron culture | BDNF | Vo et al. (2005) | |||
Cortical neuron culture | Forskolin | Klein et al. (2007) | ||||
Suprachiasmatic nuclei | Light | Cheng et al. (2007) | ||||
Hippocampal neuron culture | Bicuculline | Wayman et al. (2008) | ||||
KCl | ||||||
Hippocampus | Seizure -muscarinic receptor agonist | Nudelman et al. (2010) | ||||
Cocaine | ||||||
Contextual fear conditioning | ||||||
Olfactory bulb | Odorant exposure | |||||
Dorsal striatum | Cocaine | Im et al. (2010) | ||||
Primary visual cortex | Dark rearing or monocular deprivation | Mellios et al. (2011) | ||||
Visual cortex | Visual stimulus | Tognini et al. (2011) | ||||
Monocular deprivation | ||||||
Cortical neuron culture | BDNF | Chai et al. (2013) | ||||
miR-134 | Cortical neuron culture | BDNF | Inactivating miR-134-associated silencing complex | Schratt et al. (2006) | ||
Cortical neuron culture | BDNF | Fiore et al. (2009) | ||||
KCl | ||||||
Infralimbic prefrontal cortex | Auditory fear conditioning | Lin et al. (2011) | ||||
Fear extinction learning | ||||||
Cortical neuron culture | Bicuculline | Increase in mature miR-134 in some interneurons | Chai et al. (2013) | |||
miR-146a-5p | Hippocampal neuron culture | DHPG | Chen and Shen (2013) | |||
miR-181a | Nucleus accumbens | Cocaine | Chandrasekar and Dreyer (2009) | |||
miR-182 | Retina | Dark adaptation | Krol et al. (2010) | |||
Lateral amygdala | Auditory fear conditioning | Griggs et al. (2013) | ||||
miR-183 | Retina | Dark adaptation | Krol et al. (2010) | |||
miR-184 | Aplysia neurons | Serotonin | Rajasethupathy et al. (2009) | |||
miR-188 | Hippocampus | Chemical LTP | Lee et al. (2012) | |||
miR-204 | Retina | Dark adaptation | Krol et al. (2010) | |||
miR-206 | Medial prefrontal cortex | Prolonged alcohol exposure | Tapocik et al. (2014) | |||
miR-211 | Retina | Dark adaptation | Krol et al. (2010) | |||
miR-212 | Dorsal striatum | Cocaine | Hollander et al. (2010) | |||
Im et al. (2010) | ||||||
miR-219 | Prefrontal cortex | Acute injection of dizocilpine, NMDAR antagonist | Kocerha et al. (2009) | |||
Suprachiasmatic nuclei | Circadian rhythm, subjective day | Cheng et al. (2007) | ||||
miR-485 | Hippocampal neuron culture | Bicuculline | Cohen et al. (2011) |
. Screening studies for activity-regulated miRNAs
References | Sources | Stimulus | Protocol | miRNA detection methods |
---|---|---|---|---|
Park and Tang (2009) | Hippocampal slices | Chemical LTP | TEA (25 mM), no Mg2+, high Ca2+, 15 min | Microarray |
mGluR-LTD | DHPG (100 uM), 15 min | |||
Wibrand et al. (2010) | Hippocampal DG | Single session: 8 pulses at 400 Hz, repeated four times, 10 s interval | Microarray | |
Eacker et al. (2011) | Hippocampus | Electroconvulsive shock (synchronous depolarization) | 1 s, 100 Hz, 22 mA current | Deep sequencing |
Taqman low-density array | ||||
Kye et al. (2011) | Hippocampal CA1 | Contextual conditioning | 2 s, 0.75 mA, 3 footshock | qRT-PCR |
DIV15 hippocampal culture | Chemical stimulation | NMDA (60 uM), 5 min | ||
Bicuculline (20 uM), 1 h | ||||
Mellios et al. (2011) | Primary visual cortex | Visual deprivation | Reared with eyelid sutured from P24-28 | Microarray qRT-PCR |
Dark rearing | Reared in darkness from birth | |||
van Spronsen et al. (2013) | DIV21 hippocampal culture | Chemical LTP | Glycine (200 uM), 5 min | Microarray |
Chemical LTD | NMDA (50 uM), 5 min | |||
Prolonged decrease of synaptic activity | TTX (2 uM), 4 h or 48 h | |||
Prolonged increase of synaptic activity | Bicuculline (40 uM), 4 h or 48 h | |||
Pai et al. (2014) | Hippocampal DG | Single Session: 8 pulses at 400 Hz, repeated four times, 10 s interval | Ago2 immunoprecipitation |
Mol. Cells 2014; 37(7): 511-517
Published online July 31, 2014 https://doi.org/10.14348/molcells.2014.0132
Copyright © The Korean Society for Molecular and Cellular Biology.
Su-Eon Sim1, Joseph Bakes1, and Bong-Kiun Kaang1,2,*
1Department of Brain and Cognitive Sciences, Seoul National University, Seoul 151-747, Korea, 2Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-747, Korea
Correspondence to:*Correspondence: kaang@snu.ac.kr
MicroRNAs are non-coding short (~23 nucleotides) RNAs that mediate post-transcriptional regulation through sequence-specific gene silencing. The role of miRNAs in neuronal development, synapse formation and synaptic plasticity has been highlighted. However, the role of neuronal activity on miRNA regulation has been less focused. Neuronal activity-dependent regulation of miRNA may fine-tune gene expression in response to synaptic plasticity and memory formation. Here, we provide an overview of miRNA regulation by neuronal activity including high-throughput screening studies. We also discuss the possible molecular mechanisms of activity-dependent induction and turnover of miRNAs.
Keywords: high-throughput screening, miRNA induction, miRNA turnover, neuronal activity, NMDAR
Neuronal activity induces various cellular and molecular changes, which results in the alteration of synaptic strength. In particular, at the synapse level, each synapse shows dynamic responses to specific neuronal activity within a few minutes, which implies that fast and precise molecular machineries are indispensable (Lee et al., 2009; Matsuzaki et al., 2004; Padamsey and Emptage, 2011).
Recent studies revealed a novel post-transcriptional regulatory system using small non-coding RNAs, so-called microRNAs (miRNA), which inhibit protein synthesis by imperfect complementary binding to 3′ untranslated region (3′UTR) of target mRNAs. Transcription of miRNAs produces long primary miRNAs (pri-miRNAs), and then these are processed by Drosha to precursor miRNAs (pre-miRNAs) which form a single hairpin structure. These pre-miRNAs are exported to the cytoplasm by Exportin 5 and further processed by Dicer to ~23-nucleotide-long mature miRNAs. Mature miRNAs are loaded into the RNA-induced silencing complex (RISC) and bind to 3′UTR of target mRNAs, which results in translational repression and/or mRNA destabilization (Bartel, 2004; Im and Kenny, 2012; Xiong et al., 2013). Translational repression of mRNA driven by miRNAs is an attractive regulatory system for explaining rapid local protein synthesis in response to neuronal activity (Huber et al., 2000; Martin et al., 1997; Sutton and Schuman, 2006). The evidence from many studies showing some miRNAs are specifically enriched in dendrites and synaptosomes also implies the role of miRNAs in neuronal activity (Kye et al., 2007; Lugli et al., 2008; Schratt et al., 2006; Siegel et al., 2009).
In this review, we summarize recent studies reporting activity-dependent regulation of miRNAs and discuss how miRNAs are regulated by various types of neuronal activity.
Numerous studies have shown that miRNAs are critically regulated by neuronal activity. We summarized a decade of research showing direct regulation of miRNAs in response to various types of neuronal activity (Table 1).
The first and most studied miRNA induced by neuronal activity is miR-132. Many studies have shown a consistent increase of miR-132 after various types of neuronal activity such as brain-derived neurotrophic factor (BDNF), KCl (membrane depolarization) and bicuculline (GABAR Receptor inhibition) in cultured neurons (Chai et al., 2013; Klein et al., 2007; Vo et al., 2005; Wayman et al., 2008) and seizure, contextual fear conditioning, odorant stimulus, light, cocaine intake and visual stimulus in particular brain regions of living animals (Cheng et al., 2007; Im et al., 2010; Nudelman et al., 2010; Tognini et al., 2011). Moreover, reduced neuronal activity such as monocular deprivation in visual cortex decreases both pre- and mature miR-132, strengthening the evidence for neuronal activity-dependent miR-132 induction (Mellios et al., 2011; Tognini et al., 2011). The induction of miR-132 is regulated by cAMP response element binding protein (CREB) which is a crucial stimulus-induced transcription factor regulating many fast-response genes and playing a key role in dendritic development and synaptic plasticity. Studies using pharmacological inhibitors showed that the induction of miR-132 requires activation of NMDA receptor, CaM kinase and MEK-ERK pathways (Cheng et al., 2007; Wayman et al., 2008).
miR-212 is another CREB-dependent miRNA. The locus of miR-212 is located only 200 bases upstream from that of miR-132 and the promoter regions of both miR-132 and miR-212 have CRE sequences (Magill et al., 2010; Remenyi et al., 2013; Vo et al., 2005). There are fewer studies about miR-212 compared to miR-132. Kenny and colleagues have studied the role of miR-212 in cocaine addiction related to CREB signaling in dorsal striatum (Hollander et al., 2010; Im et al., 2010). Authors showed that miR-212 is specifically induced by extended but not restricted cocaine access and amplifying CREB signaling
The regulation of miR-134 is more complicated than other miRNAs. Schratt et al. (2006) showed that synaptodendritically localized miR-134 negatively regulates dendritic spine size by repressing the translation of target Lim-domain-containing protein kinase 1 (LimK1) mRNA. After BDNF treatment, the translation of LimK1 is increased by the relief of miR-134 inhibition, which suggests miR-134-associated silencing complex is inactivated or diminished at the synaptodendritic compartment. On the other hand, Fiore et al. showed that BDNF stimulation increases the level of pre-miR-134
The brain-enriched and highly conserved miRNA miR-124 has been studied largely for its role in neuronal development (Cao et al., 2007; Cheng et al 2009; Landgraf et al 2007; Makeyev et al., 2007; Yu et al 2008). Kandel and colleagues first demonstrated the activity-dependent regulation of miR-124 in
The study of Krol et al. (2010) provides clear evidence of dynamic regulation of miRNAs by a stimulus. Several retinal miRNAs, miR-183/96/182 cluster, miR-204 and miR-211, were dynamically up- and down-regulated by light. The levels of these miRNAs were remarkably decreased by dark adaptation and rapidly recover to their maximum levels within 30 min after return to light.
There are several screening studies looking for global changes of miRNAs after neuronal activities (Table 2).
The study of Park and Tang examined a time-dependent change in miRNAs after chemical LTP (c-LTP) or metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) in hippocampal slices. Among 237 miRNAs tested by microarray, 50 miRNAs and 59 miRNAs were increased more than 8 folds after c-LTP and mGluR-LTD stimulation, respectively. Interestingly, most of the miRNAs were increased within 15 min after c-LTP and 30 min after mGluR-LTD (Park and Tang, 2009).
The rapid induction of miRNAs was also observed in living animals. Electroconvulsive shock was given to induce massive and synchronous depolarization of hippocampal neurons. Expression levels of miRNAs measured by Taqman low-density array showed that most miRNAs were increased rapidly within 1 h (Eacker et al., 2011).
Bramham and colleagues performed microarray analysis using the high frequency stimulus (HFS) paradigm for
The study of van Spronsen et al. (2013) examined the activity-dependent change in miRNA using mature primary hippocampal neuron cultures. The authors investigated the change in 264 miRNAs after NMDA receptor-mediated synaptic plasticity or homeostatic synaptic plasticity using microarray analysis. A chemical LTP or a chemical long-term depression (LTD) protocol was used for NMDA receptor-mediated synaptic plasticity, which induced a change in expression of 51 miRNAs. For homeostatic synaptic plasticity, either voltage-gated sodium channel blocker tetrodotoxin (TTX, suppress action potential) or GABAA receptor antagonist bicuculline (increase synaptic activity) was treated for 4 h or 48 h. Prolonged change of synaptic activity in neuron culture altered the expression of 31 miRNAs.
Specific experiences may induce the changes in miRNA expression. Kye et al. (2011) studied the change in miRNAs in the hippocampus after contextual fear conditioning. The expression of 187 miRNAs in the hippocampal CA1 region was measured by quantitative real time PCR (qRT-PCR) at three different time points after training (1 h, 3 h, and 24 h). Astonishingly, a single training session significantly changed the expression level of almost half of measured miRNAs (90 miRNAs). Sur and colleagues screened miRNAs in the primary visual cortex (V1) responding to visual deprivation
Interestingly, there is a report showing that miRNA dysregulation is linked to the pathogenesis of neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) (Campos-Melo et al., 2013). This study analyzed the expression profile of 664 miRNAs in the sporadic ALS spinal cord tissues. The results showed that there is a specific group of dysregulated miRNAs and that specific miRNA dysregulation might be related to the selective suppression of neurofilament miRNA observed in sporadic ALS.
There are two possible mechanisms for the induction of miRNA (Fig. 1). The first mechanism is suggested by the finding which showed neuronal activity induces the cleavage of Dicer and increases its RNAse III activity. This study showed that enzymatically inactive Dicer is enriched at postsynaptic densities (PSD), and is released and activated by calcium-dependent calpain activation (Lugli et al., 2005). Because Dicer is a key enzyme to produce mature miRNAs, the release of active Dicer might process most of the pre-miRNAs located in dendritic spine all at once. This mechanism may explain the results of previous studies reporting fast induction of many miRNAs after stimulation (Eacker et al., 2011; Park and Tang, 2009). The second miRNA induction mechanism is
Compared to induction of miRNA, little is known of the activity-dependent neuronal miRNA turnover. This lack of attention might be related to previous studies which have shown that miRNAs are highly stable and have slow turnover rates (Bhattacharyya et al., 2006; Gantier et al., 2011; van Rooij et al., 2007). Meanwhile, Krol et al. (2010) provide a new insight into the nature of miRNA turnover, reporting that miRNAs in neuron have rapid turnover rates that are dependent on neuronal activity. The level of miRNAs in mouse retina was rapidly, within a few hours, decreased after transcriptional shut-down
Until now, almost nothing is known about the mechanism for neuronal activity-dependent miRNA turnover. One possible mechanism is the degradation of RISC by neuronal activity (Fig. 1). In
Synaptic activity across neurons is the most fundamental feature of neurons. We focused here on how neuronal activity regulates the level of miRNAs. From a decade of efforts, a good body of evidence has elucidated the mechanism of miRNA regulation. Particularly, high-throughput studies provide new insights for understanding global changes in miRNAs.
In the future, more studies about cell type-specific or neuronal circuit-specific miRNA regulation are demanded to understand the diversity and complexity of brain function.
. Neuronal activity-dependent regulation of microRNAs.
miRNA | Neuronal sources | Stimuli to induce neuronal activity | Regulation of miRNAs | References | ||
---|---|---|---|---|---|---|
Primary | Precursor | Mature | ||||
let-7d | Ventral tegmental area | Cocaine | Chandrasekar and Dreyer (2009) | |||
miR-96 | Retina | Dark adaptation | Krol et al. (2010) | |||
miR-124 | Aplysia neurons | Serotonin | Rajasethupathy et al. (2009) | |||
Caudate putamen | Cocaine | Chandrasekar and Dreyer (2009) | ||||
Ventral tegmental area | ||||||
miR-128b | Infralimbic prefrontal cortex | Fear extinction learning | Lin et al. (2011) | |||
miR-132 | Cortical neuron culture | BDNF | Vo et al. (2005) | |||
Cortical neuron culture | Forskolin | Klein et al. (2007) | ||||
Suprachiasmatic nuclei | Light | Cheng et al. (2007) | ||||
Hippocampal neuron culture | Bicuculline | Wayman et al. (2008) | ||||
KCl | ||||||
Hippocampus | Seizure -muscarinic receptor agonist | Nudelman et al. (2010) | ||||
Cocaine | ||||||
Contextual fear conditioning | ||||||
Olfactory bulb | Odorant exposure | |||||
Dorsal striatum | Cocaine | Im et al. (2010) | ||||
Primary visual cortex | Dark rearing or monocular deprivation | Mellios et al. (2011) | ||||
Visual cortex | Visual stimulus | Tognini et al. (2011) | ||||
Monocular deprivation | ||||||
Cortical neuron culture | BDNF | Chai et al. (2013) | ||||
miR-134 | Cortical neuron culture | BDNF | Inactivating miR-134-associated silencing complex | Schratt et al. (2006) | ||
Cortical neuron culture | BDNF | Fiore et al. (2009) | ||||
KCl | ||||||
Infralimbic prefrontal cortex | Auditory fear conditioning | Lin et al. (2011) | ||||
Fear extinction learning | ||||||
Cortical neuron culture | Bicuculline | Increase in mature miR-134 in some interneurons | Chai et al. (2013) | |||
miR-146a-5p | Hippocampal neuron culture | DHPG | Chen and Shen (2013) | |||
miR-181a | Nucleus accumbens | Cocaine | Chandrasekar and Dreyer (2009) | |||
miR-182 | Retina | Dark adaptation | Krol et al. (2010) | |||
Lateral amygdala | Auditory fear conditioning | Griggs et al. (2013) | ||||
miR-183 | Retina | Dark adaptation | Krol et al. (2010) | |||
miR-184 | Aplysia neurons | Serotonin | Rajasethupathy et al. (2009) | |||
miR-188 | Hippocampus | Chemical LTP | Lee et al. (2012) | |||
miR-204 | Retina | Dark adaptation | Krol et al. (2010) | |||
miR-206 | Medial prefrontal cortex | Prolonged alcohol exposure | Tapocik et al. (2014) | |||
miR-211 | Retina | Dark adaptation | Krol et al. (2010) | |||
miR-212 | Dorsal striatum | Cocaine | Hollander et al. (2010) | |||
Im et al. (2010) | ||||||
miR-219 | Prefrontal cortex | Acute injection of dizocilpine, NMDAR antagonist | Kocerha et al. (2009) | |||
Suprachiasmatic nuclei | Circadian rhythm, subjective day | Cheng et al. (2007) | ||||
miR-485 | Hippocampal neuron culture | Bicuculline | Cohen et al. (2011) |
. Screening studies for activity-regulated miRNAs.
References | Sources | Stimulus | Protocol | miRNA detection methods |
---|---|---|---|---|
Park and Tang (2009) | Hippocampal slices | Chemical LTP | TEA (25 mM), no Mg2+, high Ca2+, 15 min | Microarray |
mGluR-LTD | DHPG (100 uM), 15 min | |||
Wibrand et al. (2010) | Hippocampal DG | Single session: 8 pulses at 400 Hz, repeated four times, 10 s interval | Microarray | |
Eacker et al. (2011) | Hippocampus | Electroconvulsive shock (synchronous depolarization) | 1 s, 100 Hz, 22 mA current | Deep sequencing |
Taqman low-density array | ||||
Kye et al. (2011) | Hippocampal CA1 | Contextual conditioning | 2 s, 0.75 mA, 3 footshock | qRT-PCR |
DIV15 hippocampal culture | Chemical stimulation | NMDA (60 uM), 5 min | ||
Bicuculline (20 uM), 1 h | ||||
Mellios et al. (2011) | Primary visual cortex | Visual deprivation | Reared with eyelid sutured from P24-28 | Microarray qRT-PCR |
Dark rearing | Reared in darkness from birth | |||
van Spronsen et al. (2013) | DIV21 hippocampal culture | Chemical LTP | Glycine (200 uM), 5 min | Microarray |
Chemical LTD | NMDA (50 uM), 5 min | |||
Prolonged decrease of synaptic activity | TTX (2 uM), 4 h or 48 h | |||
Prolonged increase of synaptic activity | Bicuculline (40 uM), 4 h or 48 h | |||
Pai et al. (2014) | Hippocampal DG | Single Session: 8 pulses at 400 Hz, repeated four times, 10 s interval | Ago2 immunoprecipitation |
Meeyoung Cho, Tae-Jun Cho, Jeong Mook Lim, Gene Lee, and Jaejin Cho
Mol. Cells 2013; 35(5): 456-461 https://doi.org/10.1007/s10059-013-0083-0