Calcium‐permeable AMPA receptors containing Q/R‐unedited GluR2 direct human neural progenitor cell differentiation to neurons

Abstract

We identify calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on human neural progenitor cells (NPCs) and present a physiological role in neurogenesis. RNA editing of the GluR2 subunit at the Q/R site is responsible for making most AMPA receptors impermeable to calcium. Because a single-point mutation could eliminate the need for editing at the Q/R site and Q/R-unedited GluR2 exists during embryogenesis, the Q/R-unedited GluR2 subunit presumably has some important actions early in development. Using calcium imaging, we found that NPCs contain calcium-permeable AMPA receptors, whereas NPCs differentiated to neurons and astrocytes express calcium-impermeable AMPA receptors. We utilized reverse-transcription polymerase chain reaction and BbvI digestion to demonstrate that NPCs contain Q/R-unedited GluR2, and differentiated cells contain Q/R-edited GluR2 subunits. This is consistent with the observation that the nuclear enzyme responsible for Q/R-editing, adenosine deaminase (ADAR2), is increased during differentiation. Activation of calcium-permeable AMPA receptors induces NPCs to differentiate to the neuronal lineage and increases dendritic arbor formation in NPCs differentiated to neurons. AMPA-induced differentiation of NPCs to neurons is abrogated by overexpression of ADAR2 in NPCs. This elucidates the role of AMPA receptors as inductors of neurogenesis and provides a possible explanation for why the Q/R editing process exists.

AMPA glutamate receptors are required for sensory-organ formation and morphogenesis in the basal chordate

“…GluAs that include the R-type GluA2 subunit lack Ca 2+ permeability (13,39). In very early development, most mammalian GluAs are Ca 2+ -permeable GluAs (Ca-P GluAs), but the Ca 2+ -impermeable GluAs (Ca-I GluAs) population increases rapidly by birth, due to intensive Q/R RNA editing of the GluA2 subunit (40)(41)(42)(43)(44). Defects in this process cause serious problems (45)(46)(47)(48)(49).…”

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].…”

Impact of Actin Filament Stabilization on Adult Hippocampal and Olfactory Bulb Neurogenesis

“…Specifically, the ability of neural progenitors to sense excitation and thereby implement coupling between network activity and neurogenesis has been established. However, so far, different neurotransmitters have been implicated in this process (Deisseroth et al, 2004;Tozuka et al, 2005;Suzuki et al, 2006;Whitney et al, 2008). In an elaborate in vitro system favoring neuronal differentiation of adult NPCs, Deisseroth et al (2004) found glutamatergic excitation driving neuronal differentiation.…”

“…In the hippocampus, excitation directly promotes neurogenesis from adult neural progenitor cells ("excitation-neurogenesis coupling") (Deisseroth et al, 2004;Tozuka et al, 2005;Suzuki et al, 2006;Whitney et al, 2008). Here, we investigated Ca 2ϩ influx in neocortical and hippocampal synaptosomes (Fig.…”