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The microRNA miR-124 suppresses seizure activity and regulates CREB1 activity.

Wang W, Wang X, Chen L, Zhang Y, Xu Z, Liu J, Jiang G, Li J, Zhang X, Wang K, Wang J, Chen G, Luo J - Expert Rev Mol Med (2016)

Bottom Line: Inhibition of neuronal firing by miR-124 was associated with the suppression of mEPSC, AMPAR- and NMDAR-mediated currents, which were accompanied by decreased surface expression of NMDAR.In addition, miR-124 injection resulted in decreased activity and expression of cAMP-response element-binding protein1 (CREB1). a key regulator in epileptogenesis.Immunoprecipitation studies confirmed that the CREB1 antibody effectively precipitated CREB1 and NMDAR1 but not GLUR1 from rat brain hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology,Chongqing Key Laboratory of Neurology,The First Affiliated Hospital of Chongqing Medical University,1 Youyi Road,Chongqing 400016,China.

ABSTRACT
miR-124, a brain-specific microRNA, was originally considered as a key regulator in neuronal differentiation and the development of the nervous system. Here we showed that miR-124 expression was suppressed in patients with epilepsy and rats after drug induced-seizures. Intrahippocampal administration of a miR-124 duplex led to alleviated seizure severity and prolonged onset latency in two rat models (pentylenetetrazole- and pilocarpine-induced seizures), while miR-124 inhibitor led to shortened onset latency in pilocarpine-induced seizure rat models. Moreover, the result of local field potentials (LFPs) records further demonstrated miR-124 may have anti-epilepsy function. Inhibition of neuronal firing by miR-124 was associated with the suppression of mEPSC, AMPAR- and NMDAR-mediated currents, which were accompanied by decreased surface expression of NMDAR. In addition, miR-124 injection resulted in decreased activity and expression of cAMP-response element-binding protein1 (CREB1). a key regulator in epileptogenesis. A dual-luciferase reporter assay was used to confirm that miR-124 targeted directly the 3'UTR of CREB1 gene and repressed the CREB1 expression in HEK293T cells. Immunoprecipitation studies confirmed that the CREB1 antibody effectively precipitated CREB1 and NMDAR1 but not GLUR1 from rat brain hippocampus. These results revealed a previously unknown function of miR-124 in neuronal excitability and provided a new insight into molecular mechanisms underlying epilepsy.

No MeSH data available.


Related in: MedlinePlus

qRT–PCR analysis of miR-124 expression in the hippocampus of patients with TLE and rat models. (a) Relative quantity of mir-124 in the temporal neocortex of controls and patients with TLE. (b) Relative quantity of miR-124-3P and miR-124-5P in the hippocampus of rat models in control conditions and at different time points after seizure. *P < 0.05, compared with the control.
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fig01: qRT–PCR analysis of miR-124 expression in the hippocampus of patients with TLE and rat models. (a) Relative quantity of mir-124 in the temporal neocortex of controls and patients with TLE. (b) Relative quantity of miR-124-3P and miR-124-5P in the hippocampus of rat models in control conditions and at different time points after seizure. *P < 0.05, compared with the control.

Mentions: First we investigated the expression of miR-124 in the temporal neocortex in patients with TLE by qRT–PCR. The results showed the expression of miR-124 was significantly lower in patients with TLE than it was in controls (Fig. 1a). To test whether miR-124 is also downregulated in the hippocampus of rats after pilocarpine-induced seizures, we next determined miR-124 expression in the hippocampus of this rat model; the results showed that the relative quantity of miR-124-3p was significantly decreased at 6 h after pilocarpine-induced seizures and remained significant low for up to 1 week (Fig. 1b). Similarly, the relative quantity of miR-124-5p was also significantly decreased at 24 h after pilocarpine-induced seizures and remained significant low for up to 1 week compared with control (Fig. 1b).Figure 1.


The microRNA miR-124 suppresses seizure activity and regulates CREB1 activity.

Wang W, Wang X, Chen L, Zhang Y, Xu Z, Liu J, Jiang G, Li J, Zhang X, Wang K, Wang J, Chen G, Luo J - Expert Rev Mol Med (2016)

qRT–PCR analysis of miR-124 expression in the hippocampus of patients with TLE and rat models. (a) Relative quantity of mir-124 in the temporal neocortex of controls and patients with TLE. (b) Relative quantity of miR-124-3P and miR-124-5P in the hippocampus of rat models in control conditions and at different time points after seizure. *P < 0.05, compared with the control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836211&req=5

fig01: qRT–PCR analysis of miR-124 expression in the hippocampus of patients with TLE and rat models. (a) Relative quantity of mir-124 in the temporal neocortex of controls and patients with TLE. (b) Relative quantity of miR-124-3P and miR-124-5P in the hippocampus of rat models in control conditions and at different time points after seizure. *P < 0.05, compared with the control.
Mentions: First we investigated the expression of miR-124 in the temporal neocortex in patients with TLE by qRT–PCR. The results showed the expression of miR-124 was significantly lower in patients with TLE than it was in controls (Fig. 1a). To test whether miR-124 is also downregulated in the hippocampus of rats after pilocarpine-induced seizures, we next determined miR-124 expression in the hippocampus of this rat model; the results showed that the relative quantity of miR-124-3p was significantly decreased at 6 h after pilocarpine-induced seizures and remained significant low for up to 1 week (Fig. 1b). Similarly, the relative quantity of miR-124-5p was also significantly decreased at 24 h after pilocarpine-induced seizures and remained significant low for up to 1 week compared with control (Fig. 1b).Figure 1.

Bottom Line: Inhibition of neuronal firing by miR-124 was associated with the suppression of mEPSC, AMPAR- and NMDAR-mediated currents, which were accompanied by decreased surface expression of NMDAR.In addition, miR-124 injection resulted in decreased activity and expression of cAMP-response element-binding protein1 (CREB1). a key regulator in epileptogenesis.Immunoprecipitation studies confirmed that the CREB1 antibody effectively precipitated CREB1 and NMDAR1 but not GLUR1 from rat brain hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology,Chongqing Key Laboratory of Neurology,The First Affiliated Hospital of Chongqing Medical University,1 Youyi Road,Chongqing 400016,China.

ABSTRACT
miR-124, a brain-specific microRNA, was originally considered as a key regulator in neuronal differentiation and the development of the nervous system. Here we showed that miR-124 expression was suppressed in patients with epilepsy and rats after drug induced-seizures. Intrahippocampal administration of a miR-124 duplex led to alleviated seizure severity and prolonged onset latency in two rat models (pentylenetetrazole- and pilocarpine-induced seizures), while miR-124 inhibitor led to shortened onset latency in pilocarpine-induced seizure rat models. Moreover, the result of local field potentials (LFPs) records further demonstrated miR-124 may have anti-epilepsy function. Inhibition of neuronal firing by miR-124 was associated with the suppression of mEPSC, AMPAR- and NMDAR-mediated currents, which were accompanied by decreased surface expression of NMDAR. In addition, miR-124 injection resulted in decreased activity and expression of cAMP-response element-binding protein1 (CREB1). a key regulator in epileptogenesis. A dual-luciferase reporter assay was used to confirm that miR-124 targeted directly the 3'UTR of CREB1 gene and repressed the CREB1 expression in HEK293T cells. Immunoprecipitation studies confirmed that the CREB1 antibody effectively precipitated CREB1 and NMDAR1 but not GLUR1 from rat brain hippocampus. These results revealed a previously unknown function of miR-124 in neuronal excitability and provided a new insight into molecular mechanisms underlying epilepsy.

No MeSH data available.


Related in: MedlinePlus