Expression of the AMPA Receptor Subunits GluR1 and GluR2 is Associated with Granule Cell Maturation in the Dentate Gyrus

Abstract

The dentate gyrus produces new granule neurons throughout adulthood in mammals from rodents to humans. During granule cell maturation, defined markers are expressed in a highly regulated sequential process, which is necessary for directed neuronal differentiation. In the present study, we show that α-amino-3-hydroxy-5-methy-4-isoxazole propionate (AMPA) receptor subunits GluR1 and GluR2 are expressed in differentiated granule cells, but not in stem cells, in neonatal, and adult dentate gyrus. Using markers for neural progenitors, immature and mature granule cells, we found that GluR1 and GluR2 were expressed mainly in mature cells and in some immature cells. A time-course analysis of 5-bromo-2′-deoxyuridine staining revealed that granule cells express GluR1 around 3 weeks after being generated. In mice heterozygous for the alpha-isoform of calcium/calmodulin-dependent protein kinase II, a putative animal model of schizophrenia and bipolar disorder in which dentate gyrus granule cells fail to mature normally, GluR1 and GluR2 immunoreactivities were substantially downregulated in the dentate gyrus granule cells. In the granule cells of mutant mice, the expression of both presynaptic and postsynaptic markers was decreased, suggesting that GluR1 and GluR2 are also associated with synaptic maturation. Moreover, GluR1 and GluR2 were also expressed in mature granule cells of the neonatal dentate gyrus. Taken together, these findings indicate that GluR1 and GluR2 expression closely correlates with the neuronal maturation state, and that GluR1 and GluR2 are useful markers for mature granule cells in the dentate gyrus.

Zif268 / egr1 gene controls the selection, maturation and functional integration of adult hippocampal newborn neurons by learning

“…The present study is unique in showing that one IEG encoding an inducible transcription factor, zif268, controls major processes in the time-frame of maturation of adult newborn DGCs during the critical period within which they are selected to survive for long-term functional integration into preexisting hippocampal networks (6). The zif268-dependent selection process takes place between 2 and 3 wk of their birth, when they start to receive synaptic glutamatergic input (7,9), undergo conversion of GABA-mediated depolarization to hyperpolarization (8), and maximally develop dendritic arbors and spines (3, 7); selective maturation processes that are all impaired in the absence of zif268. This stalled and incomplete maturation of surviving newborn DGCs within this critical period is likely to be a salient functional cause of their unsuccessful recruitment and functional incorporation into memory networks, as evidenced by the failure of training in a spatial learning task to promote their survival and lack of activation upon memory recall.…”

“…We hypothesized that in the absence of zif268, the functional maturation of differentiated newborn DGCs at the time of learning may be incomplete, resulting in their recruitment failure during learning and, hence, deficient survival. To test this hypothesis, we first analyzed GluR1 expression in 21-dpi DGCs, when they start to receive glutamatergic inputs (7,9), and at the later age of 43 dpi. We found that the proportion of 21-d-old newborn DGCs expressing GluR1 was reduced in zif268-KO mice (Fig.…”

“…From the second week after birth, axons of newborn DGCs elongate (3) and contact hilar and CA3 pyramidal cells (7), then dendrites extend in the molecular layer and spines start to appear (2, 3). Newborn DGCs are initially tonically activated by ambient depolarizing GABA and then hyperpolarized after the gradual conversion of Cl − cotransporter expression (8), along with expression of glutamate receptors and their progressive responsiveness to glutamatergic inputs (8,9). At this stage, they are hyperexcitable, display properties of enhanced synaptic plasticity, and are prone to integrate the existing hippocampal neurocircuitry (10)(11)(12).…”

AMPAergic mechanisms linked to cerebral ischemia

“…In particular, AMPARs containing GluR1, GluR3 and GluR4 subunits are Ca 2+ permeable, while GluR2-containing receptors result impermeable to Ca 2+ [52] . As pointed out above, GluR1 and GluR2 are retained the main AMPAR subunits that play a pivotal role on the conduction of fast excitatory synaptic transmission during neuronal developmental processes [53] and which aside being involved with neuronal maturation activities [54] inflammatory plus painful conditions [55-56-57] together with epilepsy states [58][59] , occupy the main center stage during the different ischemic states. Studies on an in vitro model of ischemic neuronal injury showed that GluR1, as well as GluR4, are cleaved in apoptotic hippocampal cell cultures, since GluR1 is a caspase-3 preferred substrate [60] , the major form of neuronal caspase, thus suggesting its involvement on the impairment of Glu transport in the extracellular accumulation of Glu and consequently cell death [61] .…”

One aptamer, two functions: the full-length aptamer inhibits AMPA receptors, while the short one inhibits both AMPA and kainate receptors

“…The formation of aberrant mossy fiber synapses onto dentate granule cells has been suggested to induce the recruitment of kainate receptors in chronic epileptic rats. These granule cells express AMPA receptors as well, especially GluA1 and GluA2 subunits [20] . Another example of a neurological disorder that involve both AMPA and kainate receptor types is acute and chronic pain mediated through interior cingulate cortex [21,22] .…”