Corneal kindled C57BL/6 mice exhibit saturated dentate gyrus long-term potentiation and associated memory deficits in the absence of overt neuron loss

NEUROBIOLOGY OF DISEASE

卷:105

Article

Remigio, Gregory J.^1,2  Loewen, Jaycie L.^1,2  Heuston, Sage³  Helgeson, Colin⁴  White, H. Steve^1,2,5  Wilcox, Karen S.^1,2,5  West, Peter J.^1,2,5 

[1] Univ Utah, Interdept Neurosci Program, Salt Lake City, UT 84108 USA

[2] Univ Utah, Dept Pharmacol & Toxicol, Salt Lake City, UT 84108 USA

[3] Waterford Sch, Sandy, UT 84093 USA

[4] Juan Diego Catholic High Sch, Draper, UT 84020 USA

[5] Univ Utah, Anticonvulsant Drug Dev Program, Salt Lake City, UT 84108 USA

关键词: Seizures;    Corneal kindling;    Hippocampus;    Dentate gyrus;    Hyperexcitability;    Synaptic plasticity;    Cognitive deficits;    Spatial pattern processing;    Intrinsic plasticity;   

DOI  :  10.1016/j.nbd.2017.06.006

来源: Elsevier

【 摘 要 】

Memory deficits have a significant impact on the quality of life of patients with epilepsy and currently no effective treatments exist to mitigate this comorbidity. While these cognitive comorbidities can be associated with varying degrees of hippocampal cell death and hippocampal sclerosis, more subtle changes in hippocampal physiology independent of cell loss may underlie memory dysfunction in many epilepsy patients. Accordingly, animal models of epilepsy or epileptic processes exhibiting memory deficits in the absence of cell loss could facilitate novel therapy discovery. Mouse corneal kindling is a cost-effective and non-invasive model of focal to bilateral tonic-clonic seizures that may exhibit memory deficits in the absence of cell loss. Therefore, we tested the hypothesis that corneal kindled C57BL/6 mice exhibit spatial pattern processing and memory deficits in a task reliant on DG function and that these impairments would be concurrent with physiological remodeling of the DG as opposed to overt neuron loss. Following corneal kindling, C57BL/6 mice exhibited deficits in a DG-associated spatial memory test - the metric task. Compatible with this finding, we also discovered saturated, and subsequently impaired, LTP of excitatory synaptic transmission at the perforant path to DGC synapse. This saturation of LTP was consistent with evidence suggesting that perforant path to DGC synapses in kindled mice had previously experienced LTP-like changes to their synaptic weights: increased postsynaptic depolarizations in response to equivalent presynaptic input and significantly larger amplitude AMPA receptor mediated spontaneous EPSCs. Additionally, there was evidence for kindling-induced changes in the intrinsic excitability of DGCs: reduced threshold to population spikes under extracellular recording conditions and significantly increased membrane resistances observed in DGCs. Importantly, quantitative immunohistochemical analysis revealed hippocampal astrogliosis in the absence of overt neuron loss. These changes in spatial pattern processing and memory deficits in corneal kindled mice represent a novel model of seizure-induced cognitive dysfunction associated with pathophysiological remodeling of excitatory synaptic transmission and granule cell excitability in the absence of overt cell loss. (C) 2017 Elsevier Inc. All rights reserved.

【 授权许可】

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