Long-lasting effects of early-life intervention in mice on adulthood behaviour, GABA_A receptor subunit expression and synaptic clustering

Variations in the early postnatal environment of rodents produce long-term changes in responses to stress that may underlie neuropsychiatric diseases such as anxiety, depression and schizophrenia. GABA_A receptors undergo marked changes in their subunit composition during this period, involving a regionally-dependent replacement of α₂ with α₁ subunits, the so-called α-subunit switch. In this study we examined the effects of early-life environment on adulthood GABA_A receptor α₁ and α₂ subunit expression and the synaptic clustering of GABA_A receptors. Male and female mice were exposed to either 15min daily handling sessions (EH) or no intervention (NH) over postnatal day (PND) 1-14. Adulthood behavioural differences in anxiety were assessed on the elevated plus-maze. Immunoperoxidase histochemistry was used to examine the density of the α₁ and α₂ subunit proteins. Double-labelling immunofluorescence and confocal microscopy were used to study GABA_A receptor synaptic clustering. NH animals showed increased anxiety-type behaviours in the elevated plus maze relative to EH mice. NH males showed a loss of α₂ subunits from the thalamus and lower layers of the somatosensory cortex, whilst NH females showed a reduction of α₂ but increase in α₁ protein in lower layers of the primary somatosensory cortex only. The NH condition also reduced α₁ subunit expression in dentate gyrus (DG) in both males and females. Regardless of sex, NH mice showed reduced colocalisation of GABA_A receptor α₂ subunits with the synaptic marker gephyrin relative to the control condition. These findings suggest that early-life environment has long-lasting effects on GABA_A receptors, leading to long-term changes in adulthood behaviour, and are of relevance to neurodevelopmental explanations of stress-augmented neuropsychiatric disorders.