Abstract
Many animal models of temporal lobe epilepsy (TLE) exhibit altered neurogenesis arising from progenitors within the dentate gyrus subgranular zone (SGZ). Aberrant integration of new neurons into the existing circuit is thought to contribute to epileptogenesis. In particular, adult-born neurons that exhibit ectopic migration and hilar basal dendrites (HBDs) are suggested to be pro-epileptogenic. Loss of reelin signaling may contribute to these morphological changes in patients with epilepsy. We previously demonstrated that conditional deletion of the reelin adaptor protein, disabled-1 (Dab1), from postnatal mouse SGZ progenitors generated dentate granule cells (DGCs) with abnormal dendritic development and ectopic placement. To determine whether the early postnatal loss of reelin signaling is epileptogenic, we conditionally deleted Dab1 in neural progenitors and their progeny on postnatal days 7–8 and performed chronic video-EEG recordings 8–10 weeks later. Dab1-deficient mice did not have spontaneous seizures but exhibited interictal epileptiform abnormalities and a significantly reduced latency to pilocarpine-induced status epilepticus. After chemoconvulsant treatment, over 90% of mice deficient for Dab1 developed generalized motor convulsions with tonic-clonic movements, rearing, and falling compared to <20% of wild-type mice. Recombination efficiency, measured by Cre reporter expression, inversely correlated with time to the first sustained seizure. These pro-epileptogenic changes were associated with decreased neurogenesis and increased numbers of hilar ectopic DGCs. Interestingly, neurons co-expressing the Cre reporter comprised a fraction of these hilar ectopic DGCs cells, suggesting a non-cell autonomous effect for the loss of reelin signaling. We also noted a dispersion of the CA1 pyramidal layer, likely due to hypomorphic effects of the conditional Dab1 allele, but this abnormality did not correlate with seizure susceptibility. These findings suggest that the misplacement or reduction of postnatally-generated DGCs contributes to aberrant circuit development and hyperexcitability, but aberrant neurogenesis after conditional Dab1 deletion alone is not sufficient to produce spontaneous seizures.
Highlights
Mesial temporal lobe epilepsy is a common and often intractable focal epilepsy (Bender et al, 2004; Dube et al, 2012)
Perhaps most compelling is the finding that disrupting the integration of a subset of postnatal-born dentate granule cells (DGCs) by suppressing phosphatase and tensin homolog (PTEN) signaling is sufficient to produce spontaneous seizures in mice, and the affected DGCs exhibit many of the aberrant changes seen in animal models of Mesial temporal lobe epilepsy (mTLE) (Pun et al, 2012)
There is an interest in identifying signaling pathways that regulate DGC neurogenesis and whose disruption might produce mTLE
Summary
Mesial temporal lobe epilepsy (mTLE) is a common and often intractable focal epilepsy (Bender et al, 2004; Dube et al, 2012). Neurogenesis is markedly disrupted in rodent models of mTLE (Parent et al, 1997, 2006; Jessberger et al, 2005, 2007; Shapiro et al, 2005; Murphy et al, 2011, 2012), leading to the idea that aberrantly integrated adult-born neurons (namely dentate granule cells, DGCs) produce seizures (Parent and Kron, 2012; Pun et al, 2012; Bielefeld et al, 2014; Cho et al, 2015) and contribute to associated comorbidities such as cognitive dysfunction and depression (Groticke et al, 2007; Muller et al, 2009; Zhang et al, 2010; Lesting et al, 2011; Levin et al, 2012; Klein et al, 2015). There is an interest in identifying signaling pathways that regulate DGC neurogenesis and whose disruption might produce mTLE
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