Status epilepticus-induced hilar basal dendrites on rodent granule cells contribute to recurrent excitatory circuitry

Abstract

Mossy fiber sprouting into the inner molecular layer of the dentate gyrus is an important neuroplastic change found in animal models of temporal lobe epilepsy and in humans with this type of epilepsy. Recently, we reported in the perforant path stimulation model another neuroplastic change for dentate granule cells following seizures: hilar basal dendrites (HBDs). The present study determined whether status epilepticus-induced HBDs on dentate granule cells occur in the pilocarpine model of temporal lobe epilepsy and whether these dendrites are targeted by mossy fibers. Retrograde transport of biocytin following its ejection into stratum lucidum of CA3 was used to label granule cells for both light and electron microscopy. Granule cells with a heterogeneous morphology, including recurrent basal dendrites, and locations outside the granule cell layer were observed in control preparations. Preparations from both pilocarpine and kainate models of temporal lobe epilepsy also showed granule cells with HBDs. These dendrites branched and extended into the hilus of the dentate gyrus and were shown to be present on 5% of the granule cells in pilocarpine-treated rats with status epilepticus, whereas control rats had virtually none. Electron microscopy was used to determine whether HBDs were postsynaptic to axon terminals in the hilus, a site where mossy fiber collaterals are prevalent. Labeled granule cell axon terminals were found to form asymmetric synapses with labeled HBDs. Also, unlabeled, large mossy fiber boutons were presynaptic to HBDs of granule cells. These results indicate that HBDs are present in the pilocarpine model of temporal lobe epilepsy, confirm the presence of HBDs in the kainate model, and show that HBDs are postsynaptic to mossy fibers. These new mossy fiber synapses with HBDs may contribute to additional recurrent excitatory circuitry for granule cells.

Nonrandom connectivity of the epileptic dentate gyrus predicts a major role for neuronal hubs in seizures

“…This dendrite does not extend into the molecular layer but rather toward the hilus, and it synapses with mossy fibers, thereby creating excitatory circuits similar to those formed by apical dendrites (35). The percentage of GCs that have these hilar basal dendrites is relatively small, with estimates ranging from 5 to 20% of GCs (23,(35)(36)(37). Interestingly, this estimate is sufficiently large, even at its minimum, to provide enough hubs to promote hyperexcitability according to the predictions of our model.…”

“…After injury, however, a subset of GCs can be found that not only have apical dendrites but a long basal dendrite as well (23). This dendrite does not extend into the molecular layer but rather toward the hilus, and it synapses with mossy fibers, thereby creating excitatory circuits similar to those formed by apical dendrites (35). The percentage of GCs that have these hilar basal dendrites is relatively small, with estimates ranging from 5 to 20% of GCs (23,(35)(36)(37).…”

The Developmental Stage of Dentate Granule Cells Dictates Their Contribution to Seizure-Induced Plasticity

“…In addition to neuronal loss and gliosis, human and experimental mTLE pathology involves prominent dentate granule cell (DGC) abnormalities, including mossy fiber sprouting (MFS), DGCs with abnormal dendrites, and dispersed or ectopically located DGCs (Tauck and Nadler, 1985;de Lanerolle et al, 1989;Houser et al, 1990;Mello et al, 1993;Parent et al, 1997;Spigelman et al, 1998;Buckmaster and Dudek, 1999;Ribak et al, 2000;Scharfman et al, 2000;Dashtipour et al, 2001). DGC abnormalities are associated with network hyperconnectivity that may impact mTLE pathogenesis.…”

Pilocarpine-Induced Seizures Cause Selective Time-Dependent Changes to Adult-Generated Hippocampal Dentate Granule Cells

“…In epileptic animals, however, granule cells with basal dendrites are common (Spigelman et al, 1998;Buckmaster and Dudek, 1999;Yan et al, 2001). Basal dendrites are significant because they project into the dentate hilus and are innervated by granule cell axons in this region, creating recurrent excitatory circuits (Ribak et al, 2000;Austin and Buckmaster, 2004). By destabilizing the dentate gyrus, these circuits may contribute to hyperexcitability and seizures.…”

“…Similarly, ectopic granule cells, found in the dentate hilus of epileptic brains (Houser, 1990), receive inappropriate innervation and may also contribute to network destabilization (Scharfman et al, 2000;Pierce et al, 2005). Basal dendrites in epileptic animals are found most frequently on granule cells that, based on their migration pattern, are predicted to be newborn (Ribak et al, 2000;Dashtipour et al, 2001Dashtipour et al, , 2002Danzer et al, 2002). Similarly, at least some ectopic granule cells are derived from newborn cells (Jung et al, 2004;Jessberger et al, 2005;Parent et al, 2006).…”