Abstract
Numerous animal models of epileptogenesis demonstrate neuroplastic changes in the hippocampus. These changes occur not only for the mature neurons and glia, but also for the newly generated granule cells in the dentate gyrus. One of these changes, the sprouting of mossy fiber axons, is derived predominantly from newborn granule cells in adult rats with pilocarpine-induced temporal lobe epilepsy. Newborn granule cells also mainly contribute to another neuroplastic change, hilar basal dendrites (HBDs), which are synaptically targeted by mossy fibers in the hilus. Both sprouted mossy fibers and HBDs contribute to recurrent excitatory circuitry that is hypothesized to be involved in increased seizure susceptibility and the development of spontaneous recurrent seizures (SRS) that occur following the initial pilocarpine-induced status epilepticus. Considering the putative role of these neuroplastic changes in epileptogenesis, a critical question is whether similar anatomic phenomena occur after epileptogenic insults to the immature brain, where the proportion of recently born granule cells is higher due to ongoing maturation. The current study aimed to determine if such neuroplastic changes could be observed in a standardized model of neonatal seizure-inducing hypoxia that results in development of SRS. We used immunoelectron microscopy for the immature neuronal marker doublecortin to label newborn neurons and their HBDs following neonatal hypoxia. Our goal was to determine whether synapses form on HBDs from neurons born after neonatal hypoxia. Our results show a robust synapse formation on HBDs from animals that experienced neonatal hypoxia, regardless of whether the animals experienced tonic-clonic seizures during the hypoxic event. In both cases, the axon terminals that synapse onto HBDs were identified as mossy fiber terminals, based on the appearance of dense core vesicles. No such synapses were observed on HBDs from newborn granule cells obtained from sham animals analyzed at the same time points. This aberrant circuit formation may provide an anatomic substrate for increased seizure susceptibility and the development of epilepsy.
Highlights
The electron dense immunoreaction product for DCX was located in dendrites and perikaryal cytoplasm of neurons located in the granule cell layer and the subgranular zone (Figs. 1–3). These elements are considered to be from newborn neurons as indicated by previous studies (Shapiro et al, 2005; Shapiro & Ribak, 2006), and the findings are similar to those published previously for 60day-old rats (Shapiro & Ribak, 2006)
It is noteworthy that in several cases from both hypoxia groups of animals, axon terminals with more than one active zone were observed on the DCX-labeled dendrites (Figs 2 and 3)
The current study demonstrated that DCX-labeled basal dendrites are a consistent feature of rodents at postnatal day 40 and that hypoxia enhances the appearance of DCX-labeled basal dendrites from newborn neurons
Summary
Our goal was to determine whether synapses form on HBDs from neurons born after neonatal hypoxia
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