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Neurobiol Dis. 2016 Dec;96:105-114. doi: 10.1016/j.nbd.2016.09.004. Epub 2016 Sep 3.

Disrupted hippocampal network physiology following PTEN deletion from newborn dentate granule cells.

Author information

1
Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States.
2
Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Departments of Anesthesia and Pediatrics, University of Cincinnati, Cincinnati, OH 45267, United States. Electronic address: steve.danzer@cchmc.org.

Abstract

Abnormal hippocampal granule cells are present in patients with temporal lobe epilepsy, and are a prominent feature of most animal models of the disease. These abnormal cells are hypothesized to contribute to epileptogenesis. Isolating the specific effects of abnormal granule cells on hippocampal physiology, however, has been difficult in traditional temporal lobe epilepsy models. While epilepsy induction in these models consistently produces abnormal granule cells, the causative insults also induce widespread cell death among hippocampal, cortical and subcortical structures. Recently, we demonstrated that introducing morphologically abnormal granule cells into an otherwise normal mouse brain - by selectively deleting the mTOR pathway inhibitor PTEN from postnatally-generated granule cells - produced hippocampal and cortical seizures. Here, we conducted acute slice field potential recordings to assess the impact of these cells on hippocampal function. PTEN deletion from a subset of granule cells reproduced aberrant responses present in traditional epilepsy models, including enhanced excitatory post-synaptic potentials (fEPSPs) and multiple, rather than single, population spikes in response to perforant path stimulation. These findings provide new evidence that abnormal granule cells initiate a process of epileptogenesis - in the absence of widespread cell death - which culminates in an abnormal dentate network similar to other models of temporal lobe epilepsy. Findings are consistent with the hypothesis that accumulation of abnormal granule cells is a common mechanism of temporal lobe epileptogenesis.

KEYWORDS:

Dentate granule cells; Epilepsy; Hippocampus; PTEN; Perforant path

PMID:
27597527
PMCID:
PMC5102799
DOI:
10.1016/j.nbd.2016.09.004
[Indexed for MEDLINE]
Free PMC Article

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