Developmental profile of GABAA-receptors in the marmoset monkey: expression of distinct subtypes in pre- and postnatal brain

Abstract

Gamma aminobutyric acid (GABA)A-receptors are expressed in fetal mammalian brain before the onset of synaptic inhibition, suggesting their involvement in brain development. In this study, we have analyzed the maturation of the GABAA-receptor in the marmoset monkey forebrain to determine whether distinct receptor subtypes are expressed at particular stages of pre- and postnatal ontogeny. The distribution of the subunits alpha 1, alpha 2, and beta 2,3 was investigated immunohistochemically between embryonic day 100 (6 weeks before birth) and adulthood. Prenatally, the alpha 2- and beta 2,3-subunit-immunoreactivity (-IR) was prominent throughout the forebrain, whereas the alpha 1-subunit-IR appeared in selected regions shortly before birth. The alpha 2-subunit-IR disappeared gradually to become restricted to a few regions in adult forebrain. By contrast, the alpha 1-subunit-IR increased dramatically after birth and replaced the alpha 2-subunit in the basal forebrain, pallidum, thalamus, and most of the cerebral cortex. Staining for the beta 2,3-subunits was ubiquitous at every age examined, indicating their association with either the alpha 1- or the alpha 2-subunit in distinct receptor subtypes. In neocortex, the alpha 1 -subunit-IR was first located selectively to layers IV and VI of primary somatosensory and visual areas. Postnatally, it increased throughout the cortex, with the adult pattern being established only during the second year. The switch in expression of the alpha 1- and alpha 2- subunits indicates that the subunit composition of major GABAA-receptor subtypes changes during ontogeny. This change coincides with synaptogenesis, suggesting that the emergence of alpha 1- GABAA-receptors parallels the formation of inhibitory circuits. A similar pattern has been reported in rat, indicating that the developmental regulation of GABAA-receptors is conserved across species, possibly including man. However, the marmoset brain is more mature than the rat brain at the onset of alpha 1-subunit expression, suggesting that alpha 1-GABAA-receptors are largely dispensable in utero, but may be required for information processing after birth.