Glutamate enhances proliferation and neurogenesis in human neural progenitor cell cultures derived from the fetal cortex

Abstract

Excitatory amino acids such as glutamate play important roles in the central nervous system. We previously demonstrated that a neurosteroid, dehydroepiandrosterone (DHEA), has powerful effects on the cell proliferation of human neural progenitor cells (hNPC) derived from the fetal cortex, and this effect is modulated through NMDA receptor signaling. Here, we show that glutamate can significantly increase the proliferation rates of hNPC. The increased proliferation could be blocked by specific NMDA receptor antagonists, but not other glutamate antagonists for kainate-AMPA or metabotropic receptors. The NR1 subunit of the NMDA receptor was detectable in elongated bipolar or unipolar cells with small cell bodies. These NR1-positive cells were colocalized with GFAP immunoreactivity. Detection of the phosphorylation of cAMP response element-binding protein (pCREB) revealed that a subset of NR1-positive hNPC could respond to glutamate. Furthermore, we hypothesized that glutamate treatment may affect mainly the hNPC with a radial morphology and found that glutamate as well as DHEA selectively affected elongated hNPC; these elongated cells may be a type of radial glial cell. Finally we asked whether the glutamate-responsive hNPC had an increased potential for neurogenesis and found that glutamate-treated hNPC produced significantly more neurons following differentiation. Together these data suggest that glutamate stimulates the division of human progenitor cells with neurogenic potential.

Neuregulin1/ErbB4-induced migration in ST14A striatal progenitors: calcium-dependent mechanisms and modulation by NMDA receptor activation

“…NMDA at high concentrations can be cytotoxic, depending on receptor density and subunit composition [27]. NMDA could also increase cell proliferation and/or survival, as demonstrated by several groups by in vivo and in vitro experiments [28,29]. …”

Prenatal NMDA Receptor Antagonism Impaired Proliferation of Neuronal Progenitor, Leading to Fewer Glutamatergic Neurons in the Prefrontal Cortex

“…Many reports have said that the NMDA receptor has an important role in the proliferation of neuronal progenitors. Glutamate stimulation via NMDA receptors significantly increased the proliferation of human neural progenitor cells derived from the fetal frontal cortex (Suzuki et al, 2006). Neurospheres derived from the embryonic rat brain express the NR1 and NR2B subunits of the NMDA receptor and show reductions in diameter and number (Mochizuki et al, 2007).…”

Glutaminase 1 Is Essential for the Differentiation, Proliferation, and Survival of Human Neural Progenitor Cells

“…Interestingly, glutamate may have dichotomous effects on neurogenesis, depending on its concentrations. Low concentrations of exogenous glutamate (10 mM) introduced to cell or slice culture led to increased NPC proliferation and neurogenic potentials [19][20][21], whereas high concentrations of exogenous glutamate (300 mM) introduction resulted in impaired DNA synthesis and reduced cellular proliferation [25]. Second, glutamate has a direct neurotoxic effect on mature neurons [35][36][37][38].…”

“…The product of glutaminase-catalyzed reaction is glutamate, a classical and the most abundantly used excitatory neurotransmitter. Glutamate has long been implicated in the maturation of neurons [18][19][20][21]. Specifically, an in vitro study on NPCs has revealed the role of glutamate in neuronal differentiation through the activation of AMPA receptors [20].…”