Suchergebnisse

Prolonged seizures (status epilepticus, SE) may drive hippocampal dysfunction and epileptogenesis, at least partly, through an elevation in neurogenesis, dysregulation of migration and aberrant dendritic arborization of newly-formed neurons. MicroRNA-22 was recently found to protect against the development of epileptic foci, but the mechanisms remain incompletely understood. Here, we investigated the contribution of microRNA-22 to SE-induced aberrant adult neurogenesis. SE was induced by intraamygdala microinjection of kainic acid (KA) to model unilateral hippocampal neuropathology in mice. MicroRNA-22 expression was suppressed using specific oligonucleotide inhibitors (antagomir-22) and newly-formed neurons were visualized using the thymidine analog iodo-deoxyuridine (IdU) and a green fluorescent protein (GFP)-expressing retrovirus to visualize the dendritic tree and synaptic spines. Using this approach, we quantified differences in the rate of neurogenesis and migration, the structure of the apical dendritic tree and density and morphology of dendritic spines in newly-formed neurons.SE resulted in an increased rate of hippocampal neurogenesis, including within the undamaged contralateral dentate gyrus (DG). Newly-formed neurons underwent aberrant migration, both within the granule cell layer and into ectopic sites. Inhibition of microRNA-22 exacerbated these changes. The dendritic diameter and the density and average volume of dendritic spines were unaffected by SE, but these parameters were all elevated in mice in which microRNA-22 was suppressed. MicroRNA-22 inhibition also reduced the length and complexity of the dendritic tree, independently of SE. These data indicate that microRNA-22 is an important regulator of morphogenesis of newly-formed neurons in adults and plays a role in supressing aberrant neurogenesis associated with SE. ; Science Foundation Ireland (13/SIRG/2098, 17/CDA/4708 and 16/TIDA/4059 to TE, 13/SIRG/2114 to EJ-M, 17/TIDA/5002 to CR, 13/IA/1891 and 16/RC/3948 to DH and co-funded under the European Regional Development Fund and by FutureNeuro Industry partners) from the Health Research Board (HRA-POR-2015-1243 to TE); European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n 602130 (to DH), from the H2020 Marie Skłowdowksa-Curie Actions Individual Fellowship (753527 to EB), from the European Union's Horizon 2020; Comunidad de Madrid to MM-P, from Fundación ''La Caixa'' to JM-R and from Areces Foundation C-XVIII and the Minister of Science and Universities of Spain BFU2014-53654-P to MM-P ; Peer Reviewed

Prolonged seizures (status epilepticus, SE) may drive hippocampal dysfunction and epileptogenesis, at least partly, through an elevation in neurogenesis, dysregulation of migration and aberrant dendritic arborization of newly-formed neurons. MicroRNA-22 was recently found to protect against the development of epileptic foci, but the mechanisms remain incompletely understood. Here, we investigated the contribution of microRNA-22 to SE-induced aberrant adult neurogenesis. SE was induced by intraamygdala microinjection of kainic acid (KA) to model unilateral hippocampal neuropathology in mice. MicroRNA-22 expression was suppressed using specific oligonucleotide inhibitors (antagomir-22) and newly-formed neurons were visualized using the thymidine analog iodo-deoxyuridine (IdU) and a green fluorescent protein (GFP)-expressing retrovirus to visualize the dendritic tree and synaptic spines. Using this approach, we quantified differences in the rate of neurogenesis and migration, the structure of the apical dendritic tree and density and morphology of dendritic spines in newly-formed neurons.SE resulted in an increased rate of hippocampal neurogenesis, including within the undamaged contralateral dentate gyrus (DG). Newly-formed neurons underwent aberrant migration, both within the granule cell layer and into ectopic sites. Inhibition of microRNA-22 exacerbated these changes. The dendritic diameter and the density and average volume of dendritic spines were unaffected by SE, but these parameters were all elevated in mice in which microRNA-22 was suppressed. MicroRNA-22 inhibition also reduced the length and complexity of the dendritic tree, independently of SE. These data indicate that microRNA-22 is an important regulator of morphogenesis of newly-formed neurons in adults and plays a role in supressing aberrant neurogenesis associated with SE ; This work was supported by funding from Science Foundation Ireland (13/SIRG/2098, 17/CDA/4708 and 16/TIDA/4059 to TE, 13/SIRG/2114 to EJ-M, 17/TIDA/5002 to CR, 13/IA/1891 and 16/RC/3948 to DH and co-funded under the European Regional Development Fund and by FutureNeuro Industry partners) from the Health Research Board (HRA-POR-2015-1243 to TE), from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n◦ 602130 (to DH), from the H2020 Marie Skłowdowksa-Curie Actions Individual Fellowship (753527 to EB), from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement (No 766124 to TE), S2013/ICE-2958 from Comunidad de Madrid to MM-P, from Fundación ''La Caixa'' to JM-R and from Areces Foundation C-XVIII and the Minister of Science and Universities of Spain BFU2014-53654-P to MM-P