br Ca influx through glutamate receptors is thought to play

Ca2+ influx through glutamate receptors is thought to play a critical role in synaptogenesis and in the formation of neuronal circuitry during early development[45]. Because AMPA receptors might contribute to these processes, particularly at times and in cells in which NMDA receptor expression is low, an important question is whether the formation of Ca2+-permeable AMPA channels is developmentally regulated. During early postnatal life, only GluR flip splice variants are expressed in rat brain; expression of flop variants appears at a later stage[46]. The degree of RNA editing at the R/G site also varies with age through the embryonic and postnatal periods, in a subunit- and splice variant-specific manner[12]. However, changes in RNA splicing or R/G editing of AMPA receptor subunits are not expected to modify Ca2+ permeability of AMPA channels. On the other hand, editing at the Q/R site in GluR2, which is crucial for Ca2+ permeability of AMPA receptors, varies only slightly during rat ghrp 6 maturation. Q/R editing is nearly complete at all ages (Fig. 1): the unedited form is detectable only in prenatal life (E14–P0) but never exceeds 1% of total gluR2 mRNA[11]. Marked developmental changes have been described for Glu-receptor subunit expression in rat brain using in situ hybridization47, 48 and northern blot analysis[49]. gluR1, gluR2 and gluR3 mRNAs exhibit differential spatial and temporal patterns of expression in developing brain, with periods of elevated expression that correspond to times of enhanced synaptic plasticity or of increased susceptibility to glutamate toxicity during development. As a first estimate of Ca2+ permeability through AMPA receptors, we compared the levels of mRNA encoding GluR1 and GluR3 (which in the absence of GluR2 form Ca2+-permeable channels) with that of GluR2 (which limits Ca2+ permeability); the (GluR1 + GluR3)/GluR2 ratio was taken as a predictor of formation of Ca2+-permeable AMPA receptors[50]. In the neocortex, striatum and cerebellum, this ratio is high at early postnatal stages and decreases monotonically with age, suggesting that a larger proportion of Ca2+-permeable channels is formed in early neonatal rather than adult life. In the hippocampus, the ratio increases from P7–P21, after which time it declines. Thus, the synthesis of GluR2 could provide a developmental mechanism regulating Ca2+-permeable AMPA receptors at crucial times. Although the Ca2+ permeability of AMPA receptors in the developing brain has not been studied in detail, immature rat retinal ganglion cells are known to express Ca2+-permeable AMPA receptors at a well defined early developmental stage in vivo (P3–P8)[51].
During transient but severe global ischemia, observed in patients successfully resuscitated from cardiorespiratory arrest[52] or induced experimentally in animals53, 54, all forebrain areas are equally affected by oxygen and glucose deprivation but only selected neuronal populations degenerate and die (for a review, see [55]). Pyramidal cells in the CA1 subfield of the hippocampus are particularly vulnerable. However, histological evidence of neurodegeneration, exhibiting characteristics of apoptosis56, 57, 58 (but see [59]), is not observed until 48–72h after circulation has been restored. This delayed neurodegeneration, which may have clinical relevance, is thought to be triggered by a transient rise in glutamate release during the ischemic episode[60], followed by late and excessive Ca2+ influx through glutamate receptor channels3, 61. Although NMDA receptors are highly permeable to Ca2+, there is now general consensus that antagonists of AMPA receptors, such as the quinoxalinedione NBQX, appear to be much more effective than NMDA antagonists in preventing CA1 cell death following severe global ischemia, even when given as late as 24h after ischemia62, 63, 64. These observations indicate that activation of AMPA receptors is necessary, and possibly sufficient, for delayed post-ischemic degeneration and that cells are not irreversibly damaged until well after the ischemic episode.