The Role of Glutamate Transporters in Early Postnatal Hippocampal Neurogenesis
Gilley, Jennifer A.
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Adult neurogenesis has been well-characterized in the subgranular zone (SGZ) of the hippocampal dentate gyrus however, early postnatal development of the dentate gyrus and changes in the neurogenic niche during this time have not been well-studied. Using a well-characterized transgenic mouse that labels early neural progenitor cells with green fluorescent protein (GFP), we created a developmental profile of the dentate gyrus from postnatal day seven (P7) to six months of age. In addition, we determined that early progenitor populations within the developing dentate gyrus exhibit age-dependent changes in proliferation and differentiation which are controlled by cell-autonomous cues. To identify potential regulators of these phenotypes, we performed microarrays and identified several differentially expressed genes within the progenitor pools of different aged mice. GltI, a glutamate transporter, was identified as a candidate which was upregulated 10 fold in progenitors from older animals. In astrocytes, GltI and Glast are required to maintain low levels of glutamate to prevent overstimulation of glutamate receptors. In neural precursors it has been suggested that glutamate stimulates proliferation by activating metabotropic glutamate receptors (mGluRs) which leads to increased intracellular calcium, however the function of glutamate transporters on these progenitors has not been identified. To elucidate the functional role of GltI and Glast, we performed in vitro experiments in glutamate-free media. By misexpressing GltI and Glast, we show that glutamate transporters negatively regulate calcium-dependent proliferation by controlling glutamate availability to mGluRs. To address the in vivo function of glutamate transporters in injury-induced neurogenesis, we characterized their expression after hypoxic-ischemic (HI) injury and noticed prolonged upregulation of both transporters on type I cells suggesting they may be involved in hypoxic preconditioning. To address this we induced expression of glutamate transporters with HI before exposing mice to traumatic brain injury (TBI). Compared to animals only injured with TBI, mice with both injuries displayed decreased progenitor proliferation suggesting an impaired capacity for repair. We have therefore identified a novel and clinically relevant role for GltI and Glast in progenitor proliferation during development and after injury.