Long-term Effects Of Recurrent Neonatal Seizures On Expression Of GABA_A Receptor α1, β2 And γ2 Subunits In The Rat Brain

Objective: To investigate the effects of flurothyl-induced neonatal recurrent seizures on GABAA receptor (GABA_AR)β1,β2, andγ2 subunit expression in adult rat brain, and discuss the relationship between these alterations of GABA_AR subunits in mature brain and the changes of spatial memory and seizure susceptibility in adult rat.Methods: 32 7-day-old (P7) Sprague-Dawley rats were divided randomly into two groups: the control group and the seizure group. Seizures were induced by inhalant flurothyl daily in six consecutive days. On P60, rats were tested for spatial memory by using the Morris water maze task. Seizure threshold was examined by intraperitoneal injection of pentylenetetrazol (PTZ), and then brain was sampled on P75. The expressions of GABA_ARα1,β2, andγ2 subunits mRNA and protein in cerebral cortex and hippocampus were detected by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry method.Results On P64, the escape latencies in water maze of the rats in the seizure group were significantly longer than those of the control rats [(42424.3±35622.0)ms vs (40712.4±29467.6)ms, P=0.001]. On P65, the frequency of crossing target within 120s in water maze of the rats in the seizure group were significantly less than those of the control rats [(1.2±0.9) vs (3.1±1.3), P＜0.001]. There was no difference in seizures threshold between two groups on P75 [(1486.6±661.9)s vs (1840.6±647.9)s, P= 0.133]. Compared to the control rats, the expressions of GABA_ARαl subunit protein in seizure rats decreased significantly in the parietal cortex, CA1-2 and CA4 region (P＜0.05). The expressions ofα1 subunit protein in the frontal cortex and dentate gyms (DG) were no significant differences between the two groups on P75 (P＞0.05). The expressions ofβ2 subunit protein in the thalamus, CA1-4 region decreased significantly in the seizure group than those in the control group on P75 (P＜0.05). The expressions ofβ2 subunit protein in cerebral cortex and DG were similar between two groups on P75 (P＞0.05). There were also no differences in the expressions ofγ2 subunit protein in the parietal lobe, DG, and CA1-3 region between the two groups (P＞0.05). The expressions ofγ2 subunit protein in the frontal lobe and CA4 region decreased significantly in the seizure group than those in the control group (P＜0.05). The expressions ofα1 andβ2 subunits mRNA in the cerebral cortex andγ2 subunit mRNA in the hippocampus were similar between two groups (P＞0.05), but the expressions ofα1 andβ2 subunits mRNA in the hippocampus andγ2 subunit mRNA in the cerebral cortex in the seizure group decreased significantly those in the control group (P＜0.05).Conclusions Recurrent seizures in neonatal rats modify GABA_A receptorα1,β2, andγ2 subunits expression in the cerebral cortex and hippocampus of adult rats, and cause long-term cognitive deficit. This phenomenon raised the possibility that abnormal GABA_A receptor expression might play an important role in long-term cognitive deficit induced by early life recurrent seizures.