Glutamate Promotes Proliferation of Striatal Neuronal Progenitors by an NMDA Receptor-Mediated Mechanism

Abstract

Increasing evidence suggests that classical neurotransmitters play important roles in the development of the mammalian CNS. We used in vivo and in vitro models to identify a novel role for glutamate in striatal neurogenesis mediated by NMDA receptors. In utero exposure to NMDA receptor antagonists during striatal neurogenesis caused a dramatic reduction in the total number of adult striatal neurons. In contrast, embryos exposed to NMDA receptor antagonists immediately after the main period of neurogenesis showed no significant change in neuronal number in the adult striatum. In addition, examination of embryos shortly after NMDA receptor blockade revealed reduced proliferation in the lateral ganglionic eminence (LGE). In culture, dividing neuronal progenitors derived from the embryonic LGE showed marked reduction in 5Ј-bromodeoxyuridine (BrdU) uptake when exposed to NMDA receptor antagonists, indicating reduced DNA synthesis. Low concentrations of NMDA significantly increased proliferation, whereas high concentrations were toxic. AMPA-KA receptor antagonists had no significant effect on striatal neuroblast proliferation either in vivo or in vitro. These results support the hypothesis that glutamate plays a novel role during early development of the ventral telencephalon, promoting proliferation of striatal neuronal progenitors by an NMDA receptor-dependent mechanism. In contrast, previous findings suggest that proliferation of cortical progenitors derived from the dorsal telencephalon is regulated by activation of AMPA-KA but not NMDA receptors. Heterogeneous responses to glutamate in different germinal zones of the telencephalon may be an important mechanism contributing to generating neuronal diversity in the forebrain.

Elevated dopamine levels during gestation produce region-specific decreases in neurogenesis and subtle deficits in neuronal numbers

“…ANOVA did not reveal significant differences among the 3 experimental groups in total numbers of NeuNpositive or NeuN-negative cells in any of the regions analyzed. Our estimates of total cell numbers in the caudate putamen and frontal cortex are consistent with estimates by others [29,40,48]. However, we were concerned that the penetration of the NeuN or the secondary antibody into the histological sections during the immunohistochemistry procedure may be uneven or incomplete (i.e.…”

“…An unbiased stereological technique, the optical fractionator [29,30,68], was used to estimate the total number of NeuN-positive and NeuN-negative cells in the caudate-putamen and frontal cortex [29,30]. The equipment consisted of a light microscope (Nikon E2000) connected to a cool CCD camera (Microfire; Optronics, Goleta, CA), motorized X-Y stage (Ludl Electronics Products, Hawthorne, NY), z-axis indicator (MT12 microcator; Heidenhain, Traunreut, Germany), and a computer running Stereo Investigator software (Microbrightfield, Inc., Colchester, VT).…”

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].…”

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

“…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). Furthermore, the activation of NMDA receptors increases the proliferation of neuronal progenitors in the developing hippocampus (Joo et al, 2007) and striatum (Luk et al, 2003) as well. These findings are consistent with the present results.…”