Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in adults, has a critical contribution to balanced excitatory-inhibitory networks in the brain. Alteration in depolarizing action of GABA during early life is connected to a wide variety of neurodevelopmental disorders. Additionally, the effects of postnatal GABA blockade on neuronal synaptic plasticity are not known and therefore, we set out to determine whether postnatal exposure to bicuculline, a competitive antagonist of GABAA receptors, affects electrophysiologic changes in hippocampal CA1 neurons later on. To this end, male and female Wistar rats received vehicle or bicuculline (300 μg/kg) on postnatal days (PNDs) 7, 9 and 11, and then underwent different behavioral and electrophysiological examinations in adulthood. Postnatal exposure to bicuculline did not affect basic synaptic transmission but led to a pronounced decrease in paired-pulse facilitation (PPF) in CA1 pyramidal neurons. Bicuculline treatment also attenuated the long-term potentiation (LTP) and long-term depression (LTD) of CA1 neurons accompanied by decreased theta-burst responses in male and female adult rats. These electrophysiology findings together with the reduced brain-derived neurotrophic factor (BDNF) levels in the hippocampus and prefrontal cortex reliably explain the disturbance in spatial reference and working memories of bicuculline-treated animals. This study suggests that postnatal GABAA blockade deteriorates short- and long-term synaptic plasticity of hippocampal CA1 neurons and related encoding of spatial memory in adulthood.

Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the mature brain. At an early developmental period, it acts in an excitatory manner that influences many processes of proliferation, migration, and differentiation of the neurons. Previous evidence indicated that manipulation of the GABAergic system function by activation or blockade of its receptors during developmental periods leads to behavioral and cognitive abnormality in adulthood. Therefore, we examined the effects of neonatal blockade of GABA-A receptors by bicuculline on behavior, cognitive function, and hippocampal and prefrontal cortex (PFC) brain-derived neurotrophic factors level (BDNF) in adulthood. As a result, neonatal rats were treated with either bicuculline (75,150, and 300 μg/kg) or DMSO on postnatal days 7,9, and 11. These groups underwent the behavioral (open field, elevated plus maze, and hot plate) and learning and memory (passive avoidance learning and memory) tests in postnatal days (PNDs) 61-70. After the ending of the behavioral tests, the rats were sacrificed under deep anesthesia and the hippocampi and prefrontal cortex (PFC) of the brain were removed for assessing the BDNF mRNA expression. Our results indicated that neonatal administration of bicuculline at the highest dose increased passive avoidance memory and hippocampal BDNF level. Meanwhile, this drug at a low dose impaired this type of memory and increased PFC BDNF level. Besides, treatment with bicuculline during postnatal days increased anxiety and pain sensitivity in a dose-dependent manner. Taken together, these findings confirmed the notion that GABA-A receptors during the developmental period are important for programming neurobehavioral phenotypes in adult life.