Abstract
In a mouse model of temporal lobe epilepsy, multicellular calcium imaging revealed that disease emergence was accompanied by massive amplification in the normally sparse, afferent stimulation-induced activation of hippocampal dentate granule cells. Patch recordings demonstrated reductions in local inhibitory function within the dentate gyrus at time points where sparse activation was compromised. Mimicking changes in inhibitory synaptic function and transmembrane chloride regulation was sufficient to elicit the dentate gyrus circuit collapse evident during epilepsy development. Pharmacological blockade of outward chloride transport had no effect during epilepsy development, and significantly increased granule cell activation in both control and chronically epileptic animals. This apparent occlusion effect implicates reduction in chloride extrusion as a mechanism contributing to granule cell hyperactivation specifically during early epilepsy development. Glutamine plays a significant role in local synthesis of GABA in synapses. In epileptic mice, sparse granule cell activation could be restored by glutamine application, implicating compromised GABA synthesis. Glutamine had no effect on granule cell activation earlier, during epilepsy development. We conclude that compromised feedforward inhibition within the local circuit generates the massive dentate gyrus circuit hyperactivation evident in animals during and following epilepsy development. However, the mechanisms underlying this disinhibition diverge significantly as epilepsy progresses.
Highlights
In a mouse model of temporal lobe epilepsy, multicellular calcium imaging revealed that disease emergence was accompanied by massive amplification in the normally sparse, afferent stimulationinduced activation of hippocampal dentate granule cells
We previously have shown that Oregon Green BAPTA-1 (OGB) used in this study is capable of detecting single action potentials (APs) in hippocampal neurons[26,27]
Using multicellular calcium imaging (MCI), we found that epilepsy development was accompanied by massive enhancement of the normally sparse activation of dentate granule cells (DGCs)
Summary
In a mouse model of temporal lobe epilepsy, multicellular calcium imaging revealed that disease emergence was accompanied by massive amplification in the normally sparse, afferent stimulationinduced activation of hippocampal dentate granule cells. Situated as the initial component of the canonical trisynaptic circuit, the dentate gyrus (DG) is a critical entry point to the hippocampus, regulating access of cortical input to the limbic system Essential to this role are the sparse, selective activation properties of the DG’s principal cells, dentate granule cells (DGCs). Alterations include sprouting of recurrent mossy fiber synapses[16], molecular and cellular alterations of local inhibitory circuits[17,18,19,20,21], aberrant neurogenesis[22], astrocytic gliosis[23], and alterations in the intrinsic properties of DGCs24 This aggregation of cellular and circuit changes in the DG accompanying epilepsy development has generated a prevalent hypothesis that its normal gating function is compromised, and this, in turn, may contribute to increased seizure propensity. DG gate failure has primarily been described using field potential recordings, which are not cell-specific and do not identify cellular mechanisms underlying this epilepsy-associated circuit collapse
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
