Abstract
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.
Highlights
Temporal lobe epilepsy (TLE) is the most common form of drug-refractory acquired epilepsy in adults (Ramey et al, 2013)
Epilepsy develops in all mice following a short latent period of 2–5 days with mice typically experiencing between 1–5 SRS per day (Mouri et al, 2008)
In situ hybridization revealed that miR-22 was evident in the subgranular zone of the dentate gyrus (DG) corresponding to sites of enhanced neurogenesis after status epilepticus (SE) (Figure 1C)
Summary
Temporal lobe epilepsy (TLE) is the most common form of drug-refractory acquired epilepsy in adults (Ramey et al, 2013). A diverse set of molecular, cellular and structural changes are consistently found in the hippocampal formation of patients and animal models of TLE, which are implicated in the formation of a network with increased excitability and a lower threshold for seizure generation (Pitkänen and Lukasiuk, 2009). Amongst these epileptogenic processes are changes in receptor expression, the formation of aberrant synaptic connections, gliosis, selective cell loss and alterations to adult hippocampal neurogenesis (AHN; Pitkänen and Lukasiuk, 2009; Jessberger and Parent, 2015). This includes the aberrant migration of a subpopulation of newly-formed dentate granule cells into the dentate hilus, where they form a population of ectopic granule cells (Parent et al, 1997)
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