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

摘要

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 alpha 2 with alpha 1 subunits, the so-called a-subunit switch. In this study we examined the effects of early-life environment on adulthood GABA(A) receptor at and alpha 2 subunit expression and the synaptic clustering of GABA(A) receptors. Male and female mice were exposed to either 15 min 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 at and alpha 2 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 alpha 2 subunits from the thalamus and lower layers of the somatosensory cortex, whilst NH females showed a reduction of alpha 2 but increase in al protein in lower layers of the primary somatosensory cortex only. The NH condition also reduced at subunit expression in dentate gyrus (DG) in both males and females. Regardless of sex, NH mice showed reduced colocalisation of GABAA receptor alpha 2 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. (C) 2017 Elsevier Ltd. All rights reserved.