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Loss of hippocampal interneurons and epileptogenesis: a comparison of two animal models of acquired epilepsy

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Abstract

Reduced hippocampal GABAergic inhibition is acknowledged to be associated with epilepsy. However, there are no studies that had quantitatively compared the loss of various interneuron populations in different models of epilepsy. We tested a hypothesis that the more severe the loss of hippocampal interneurons, the more severe was the epilepsy. Epileptogenesis was triggered in adult rats by status epilepticus (SE) (56 SE, 24 controls) or by traumatic brain injury (TBI) (45 TBI, 23 controls). The total number of hippocampal parvalbumin (PARV), cholecystokinin (CCK), calretinin (CR), somatostatin (SOM), or neuropeptide Y (NPY) positive neurons was estimated using unbiased stereology at 1 or 6 months post-insult. The rats with TBI had no spontaneous seizures but showed increased seizure susceptibility. Eleven of the 28 rats (39 %) in the SE group had spontaneous seizures. The most affected hippocampal area after TBI was the ipsilateral dentate gyrus, where 62 % of PARV-immunoreactive (ir) (p < 0.001 compared to controls), 77 % of CR-ir (p < 0.05), 46 % of SOM-ir (p < 0.001), and 59 % of NPY-ir (p < 0.001) cells remained at 1 month after TBI. At 6 months post-TBI, only 35 % of PARV-ir (p < 0.001 compared to controls), 63 % of CCK-ir (p < 0.01), 74 % of CR-ir (p < 0.001), 55 % of SOM-ir (p < 0.001), and 51 % of NPY-ir (p < 0.001) cells were remaining. Moreover, the reduction in PARV-ir, CCK-ir, and CR-ir neurons was bilateral (all p < 0.05). Substantial reductions in different neuronal populations were also found in subfields of the CA3 and CA1. In rats with epilepsy after SE, the number of PARV-ir neurons was reduced in the ipsilateral CA1 (80 % remaining, p < 0.05) and the number of NPY-ir neurons bilaterally in the dentate gyrus (33–37 %, p < 0.01) and the CA3 (54–57 %, p < 0.05). Taken together, interneuron loss was substantially more severe, widespread, progressive, and included more interneuron subclasses after TBI than after SE. Interneurons responsible for perisomatic inhibition were more vulnerable to TBI than those providing dendritic inhibition. Unlike expected, we could not demonstrate any etiology-independent link between the severity of hippocampal interneuron loss and the overall risk of spontaneous seizures.

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Acknowledgments

This study was supported by the FP6 Grant LSHM-CT-2006-037315 (A.P.), Academy of Finland (A.P.), The Sigrid Juselius Foundation (A.P.), The North-Savo Regional Fund of The Finnish Cultural Foundation (N.H.), and The Finnish Epilepsy Foundation (N.H.). We thank Mr Jarmo Hartikainen and Mrs Merja Lukkari for their excellent technical assistance.

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The authors declare that they have no conflict of interest.

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  1. Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211, Kuopio, Finland

    Noora Huusko, Christine Römer, Xavier Ekolle Ndode-Ekane & Asla Pitkänen

  2. The Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Str, 02-093, Warsaw, Poland

    Katarzyna Lukasiuk

  3. Department of Neurology, Kuopio University Hospital, PO Box 1777, 70211, Kuopio, Finland

    Asla Pitkänen

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  1. Noora Huusko
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429_2013_644_MOESM8_ESM.pdf

Online Resource 8. Supplementary Figure 1. Representative examples of substance P receptor (SPR) immunoreactivity (ir) in the ipsilateral septal dentate gyrus in three rats. Percentages in panels B and C indicate the magnitude in reduction of PARV immunolabeled neurons in different layers of the dentate gyrus after TBI. (A) A control rat. Arrows indicate numerous SPR-ir somata with immunopositive dendrites in the granule cell and molecular layers, and a dense fiber plexus in the hilus. (B) A rat with TBI 1 month earlier. The animal had 50% of PARV-ir neurons remaining in the ipsilateral dentate gyrus at 1 month post-TBI. Laminar analysis revealed that the rat had 91% (-9%) of PARV-ir neurons remaining in the molecular layer, 71% (-29%) in the granule cell layer, and 56% (-44%) in the hilus as compered to the control mean. Note a reduction in SPR-ir neurons and immunopositive fibers in the infragranular region and the hilus, respectively, as compared to the control rat (panel A). Arrows indicate some of the remaining SPR-ir somata. (C) A rat with TBI 6 months earlier. The animal had 35% of PARV-ir neurons remaining in the ipsilateral dentate gyrus at 6 months post-TBI. Laminar analysis revealed that the rat had 79% (-21%) of PARV-ir neurons remaining in the molecular layer, 36% (-64%) in the granule cell layer and 18% (-88%) in the hilus as compered to the control mean. Arrows indicate two remaining SPR-ir somata. Abbreviations: GCL, granule cell layer; H, hilus; MOL, molecular layer; TBI, traumatic brain injury. Scale bar equal 50 µm in all panels. (PDF 423 kb)

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Huusko, N., Römer, C., Ndode-Ekane, X.E. et al. Loss of hippocampal interneurons and epileptogenesis: a comparison of two animal models of acquired epilepsy. Brain Struct Funct 220, 153–191 (2015). https://doi.org/10.1007/s00429-013-0644-1

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