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.

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

“…Normally in development, an increase in α1 subunit expression is paired with a decrease in α2 subunits after the first few weeks of postnatal development. This switch from α2 to α1 subunit expression coincides with the formation of synapses and is associated with the beginning of synaptic inhibition (Hornung and Fritschy, 1996). Therefore, the α1 down-regulation we observed in Fmr1 knockout mice (during the excitatory period) may lead to a disruption of the developmental switch in excitation/inhibition and synapse formation.…”

“…The α1β2γ2 subtype is the most abundant GABA A receptor in the mature CNS, comprising roughly 50% of all GABA A receptors (Mohler, 2007). Unlike the α1 subunit, expression of β2 is relatively high in the early postnatal period of wild-type mice (Hornung and Fritschy, 1996). Thus, we may normally expect to see an increase in the association of β2 subunits with α1 subunits as the expression of α1 rapidly increases in the first few weeks of postnatal life.…”

Postnatal maturation of GABAergic transmission in the rat basolateral amygdala

“…Expression of the ␣1-subunit, among others, emerged at P21, confirming results found with mRNA from whole BLA (Zhang et al 1992). This change is well documented throughout the brain and is known to contribute to the faster kinetics observed with age (Bosman et al 2002;Davis et al 2000;Dunning et al 1999;Eyre et al 2012;Hornung and Fritschy 1996;Mohler et al 2004;Okada et al 2000;Vicini et al 2001). Developmental changes in subunit expression are also known to regulate channel localization and drug sensitivity (Hevers and Luddens 2002;Nusser et al 1996).…”

GABAAReceptor β3 Subunit Deletion Decreases α2/3 Subunits and IPSC Duration

“…Fast IPSCs in ␤3 Ϫ/Ϫ mice may underlie the generalized seizures reported in behavioral studies of these mice (DeLorey et al 1998;Homanics et al 1997). Additionally, given the pivotal role of GABA in early development (Maric et al 2001) and the high expression of ␣2-and ␣3-containing receptors at early stages in life (Hornung and Fritschy 1996;Laurie et al 1992;Poulter et al 1992), the reduction of expression of receptors containing these subunits may possibly be related to the severe developmental malformation and behavioral impairment observed in these mice.…”