The Influence of Ectopic Migration of Granule Cells into the Hilus on Dentate Gyrus-CA3 Function

Abstract

Postnatal neurogenesis of granule cells (GCs) in the dentate gyrus (DG) produces GCs that normally migrate from the subgranular zone to the GC layer. However, GCs can mismigrate into the hilus, the opposite direction. Previous descriptions of these hilar ectopic GCs (hEGCs) suggest that they are rare unless there are severe seizures. However, it is not clear if severe seizures are required, and it also is unclear if severe seizures are responsible for the abnormalities of hEGCs, which include atypical dendrites and electrophysiological properties. Here we show that large numbers of hEGCs develop in a transgenic mouse without severe seizures. The mice have a deletion of BAX, which normally regulates apoptosis. Surprisingly, we show that hEGCs in the BAX-/- mouse have similar abnormalities as hEGCs that arise after severe seizures. We next asked if there are selective effects of hEGCs, i.e., whether a robust population of hEGCs would have any effect on the DG if they were induced without severe seizures. Indeed, this appears to be true, because it has been reported that BAX-/- mice have defects in a behavior that tests pattern separation, which depends on the DG. However, inferring functional effects of hEGCs is difficult in mice with a constitutive BAX deletion because there is decreased apoptosis in and outside the DG. Therefore, a computational model of the normal DG and hippocampal subfield CA3 was used. Adding a small population of hEGCs (5% of all GCs), with characteristics defined empirically, was sufficient to disrupt a simulation of pattern separation and completion. Modeling results also showed that effects of hEGCs were due primarily to “backprojections” of CA3 pyramidal cell axons to the hilus. The results suggest that hEGCs can develop for diverse reasons, do not depend on severe seizures, and a small population of hEGCs may impair DG-dependent function.

Aberrant hippocampal neurogenesis after limbic kindling: Relationship to BDNF and hippocampal-dependent memory

“…Our observations that limbickindled rats had significantly more BrdU-ir hilar-CA3 ectopic granule cells and DCX-ir neurons containing hilar basal dendrites paralleled significant memory impairments on the trace fear conditioning memory test. It was recently shown that the presence of a small population of hilar-CA3 ectopic granule cells can disrupt pattern separation and completion-processes that are critical for hippocampal-dependent spatial learning and memory [63]. Our behavioral results in combination with our postmortem analyses support this notion.…”

Altered hippocampal neurogenesis during the first 7 days after a fluid percussion traumatic brain injury

“…In the case of seizures, hilar ectopic granule cells have been demonstrated to contribute to a hyperexcitable recurrent hippocampal circuitry. 32,33 This circuit has also been demonstrated anatomically [15][16][17] and in previous studies using the same FPI model. It has been demonstrated that this model has anatomical alterations consistent with aberrant hippocampal circuitry.…”

Corruption of the dentate gyrus by “dominant” granule cells: Implications for dentate gyrus function in health and disease

“…Rodents are the focus here. In Figure 1, several elements of the fundamental circuitry are simplified or collapsed for implementation in a computational model of the DG and CA3 (Myers & Scharfman, 2011; Myers et al, 2013). In brief, the primary glutamatergic input from cortex is the perforant path, formed by axons of neurons of layer II of the entorhinal cortex.…”