Changes in hippocampal GABA_A/cBZR density during limbic epileptogenesis: Relationship to cell loss and mossy fibre sprouting

Reduced GABA_A/central benzodiazepine receptor (GABA_A/cBZR) density, mossy fibre sprouting (MFS) and hippocampal cell loss are well described pathological features of human temporal lobe epilepsy (TLE), and animal models thereof. However, the temporal relationship of their development, and their roles in the emergence of the epilepsy, are uncertain. This was investigated in the kainic acid (KA)-induced post-status epilepticus (SE) model of TLE. Male Wistar rats (7weeks, n=53) were randomised into control and KA groups. At 24h, 2, 4 or 6weeks sham and KA post-SE animals were euthanised, brains extracted and GABA_A/cBZR density, neuronal loss and MFS measured in hippocampal sub-regions. GABA_A/cBZR density (B_max) was measured by saturation-binding analysis using [³H]-flumazenil. At 24h post-SE GABA_A/cBZR density was increased in almost all hippocampal subregions, but was decreased at the later time points with the exception of the dentate gyrus. There was significant neuronal loss in the CA3 SPc region (-24±9.3%, p<0.05) at 24h, which remained stable at the later time points associated with an elevated GABA_A/cBZR density per surviving neuron at 24h post-SE (+56.4%; p<0.05) which returned to control levels by 6 weeks post-SE. MFS in the dentate gyrus progressively increased over the 6weeks following SE (+70.6% at 6weeks), at which time there was a significant inverse relationship with GABA_A/cBZR binding (r²=0.87; p=0.02). The temporal evolution of GABA_A/cBZR density changes post-KA-induced SE, and the relationship with decreases in hippocampal pyramidal cell numbers and MFS, may point to a key role for these changes in the pathogenesis of acquired limbic epileptogenesis.