Long-lasting effects of early-life intervention in mice on adulthood behaviour, GABA 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 receptors undergo marked changes in their subunit composition during this period, involving a regionally-dependent replacement of α with α subunits, the so-called α-subunit switch. In this study we examined the effects of early-life environment on adulthood GABA receptor α and α subunit expression and the synaptic clustering of GABA 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 α and α subunit proteins. Double-labelling immunofluorescence and confocal microscopy were used to study GABA 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 α subunits from the thalamus and lower layers of the somatosensory cortex, whilst NH females showed a reduction of α but increase in α protein in lower layers of the primary somatosensory cortex only. The NH condition also reduced α subunit expression in dentate gyrus (DG) in both males and females. Regardless of sex, NH mice showed reduced colocalisation of GABA receptor α subunits with the synaptic marker gephyrin relative to the control condition. These findings suggest that early-life environment has long-lasting effects on GABA receptors, leading to long-term changes in adulthood behaviour, and are of relevance to neurodevelopmental explanations of stress-augmented neuropsychiatric disorders.