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

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.

Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using 18F-GE-179 and 18F-GE-194 Autoradiography

“…A clear decrease in GABA-A receptor a1 was evident by 40-42 d after TBI. These observations suggest a progressive decrease in thalamic GABA-A receptor density that is consistent with our current histologic analysis of the progression of GABAergic neuronal pathology as well as with our recent real-time polymerase chain reaction, gene array, and immunohistochemical analyses of GABA-A receptor subunits in the same model of TBI (26,27). The decrease in GABA receptors in the thalamus detected with 18 F-GE-194 may also underlie the increase in NMDA activity in the same area revealed by 18 F-GE-179.…”

Interneuron Transplantation as a Treatment for Epilepsy

“…For example, specific populations of interneurons in the hippocampus, primarily SST-positive interneurons, are lost in patients with temporal lobe epilepsy (Babb et al 1989;de Lanerolle et al 1989;Houser 1990;Mathern et al 1995;Zhu et al 1997;Andrioli et al 2007), as well as brain trauma patients that develop limbic epilepsy (Swartz et al 2006); this finding has been replicated in multiple animal models of pharmacologically induced temporal lobe epilepsy (Obenaus et al 1993;Buckmaster and Dudek 1997;Buckmaster and Jongen-Rêlo 1999;Kobayashi and Buckmaster 2003) and traumatic brain injury (Lowenstein et al 1992;Toth et al 1997;Huusko et al 2015). The presence of substantial and widespread interneuron loss in damaged regions of the cortex in acquired epilepsy is almost always linked to a subsequent reduction in synaptic inhibition (Kobayashi and Buckmaster 2003;Hunt et al 2010), as well as putative compensatory responses of damaged inhibitory circuits (e.g., interneuron axon sprouting and changes in GABA receptor subunit composition).…”

Demographic and Clinical Findings of Epilepsy Patients who Underwent Follow-up at the Newly Established Clinic of the Muğla Sıtkı Koçman University Faculty of Medicine

“…[6,7] Travma sonrası epilepside altta yatan mekanizma tam olarak bilinmemekle birlikte, yapılan deneysel çalışmalarda GABA-A kanal ve glutamat sinyalizasyonundaki değişikliklerin travmatik beyin hasarını izleyen erken dönem nöbetlerde rol oynayabileceğine dair kanıtlar vardır. [6,8] Febril konvülziyon öyküsü olan hastalarda epilepsi gelişme riski yaklaşık %3'tür. [9] Epilepsi gelişim riski en çok komplike febril nöbette artar.…”