Excitatory amino acid transporter 2 and excitatory amino acid transporter 1 negatively regulate calcium-dependent proliferation of hippocampal neural progenitor cells and are persistently upregulated after injury

Using a transgenic mouse (Mus musculus) in which nestin-expressing progenitors are labeled with enhanced green fluorescent protein, we previously characterized the expression of excitatory amino acid transporter 2 (GltI) and excitatory amino acid transporter 1 (Glast) on early neural progenitors in vivo. To address their functional role in this cell population, we manipulated their expression in P7 neurospheres isolated from the dentate gyrus. We observed that knockdown of GltI or Glast was associated with decreased bromodeoxyuridine incorporation and neurosphere formation. Moreover, we determined that both glutamate transporters regulated progenitor proliferation in a calcium-dependent and metabotropic glutamate receptor-dependent manner. To address the relevance of this in vivo, we utilized models of acquired brain injury, which are known to induce hippocampal neurogenesis. We observed that GltI and Glast were specifically upregulated in progenitors following brain injury, and that this increased expression was maintained for many weeks. Additionally, we found that recurrently injured animals with increased expression of glutamate transporters within the progenitor population were resistant to subsequent injury-induced proliferation. These findings demonstrate that GltI and Glast negatively regulate calcium-dependent proliferation in vitro and that their upregulation after injury is associated with decreased proliferation after brain trauma.