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

Abstract

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. GABAA 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 GABAA receptor α1 and α2 subunit expression and the synaptic clustering of GABAA 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 GABAA 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 GABAA 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 GABAA receptors, leading to long-term changes in adulthood behaviour, and are of relevance to neurodevelopmental explanations of stress-augmented neuropsychiatric disorders.