Phosphorylation of extracellular‐regulating kinase in NMDA receptor antagonist‐induced newly generated neurons in the adult rat dentate gyrus

Abstract

Neurogenesis in the adult brain is promoted by various stimulations. NMDA receptor blockade enhances neurogenesis in the hippocampal dentate gyrus. There is no agreed conclusion, however, as to whether newly generated neurons after NMDA receptor blockade obtain functional properties. We investigated the functional maturation of newly generated neurons after NMDA receptor blockade. In the dentate gyrus, 80% of newly generated cells differentiated into the phenotype of mature neurons at 29 days after the single intraperitoneal injection of an NMDA receptor antagonist MK-801. The number of newly generated neurons after MK-801 treatment was significantly greater than that in the saline-treated group. The neurogenic basic helix-loop-helix transcription factor NeuroD protein in the dentate gyrus after MK-801 treatment was expressed transiently in proliferative cells, but not in mature neurons. To determine functional properties of newly generated neurons, we administered NMDA to the lateral ventricle. As an in vivo response, we assessed extracellularregulating kinase (ERK) phosphorylation. The newly generated neurons showed ERK phosphorylation by NMDA administration as seen in surrounding mature neurons. The number of newly generated neurons, which responded to NMDA receptor stimulation, increased with time after MK-801 treatment. The present study provides evidence that newly generated neurons in the adult hippocampus after NMDA receptor blockade acquire biochemical function in vivo.

Methamphetamine decreases dentate gyrus stem cell self-renewal and shifts the differentiation towards neuronal fate

“…Moreover, administration of NMDA (30 mg/kg) to Sprague-Dawley rats decreased the population of proliferating cells in the DG, whereas administration of MK-801 or CGP37849 resulted in the opposite effect (Cameron et al, 1995). Also, MK-801 administration (3 mg/kg) to NMDA-infused (2 mg/ml) Wistar rats increases the phosphorylated levels of ERK in newly generated neurons (Okuyama et al, 2004), which strengths the involvement of NMDA receptors in decreasing cell proliferation through regulation of the MAPK pathway. Moreover, Deisseroth et al (2004) demonstrated that NMDA receptors play an active role in neuronal differentiation, showing that excitatory stimuli induced by NMDA receptor activation enhances expression of NeuroD, a downstream regulator of neuronal differentiation, and consequently increases neurogenesis in neural progenitor cells culture.…”

Long-Term Potentiation Enhances Neurogenesis in the Adult Dentate Gyrus

“…In view of reports indicating that blocking NMDAR promotes adult neurogenesis (Cameron et al, 1995;Okuyama et al, 2004) it is surprising that LTP enhanced the rate of neurogenesis. However, our results are consistent with recent findings showing strong depolarization or glutamate activation can impinge on proliferating adult DG precursor cells and, in vivo, increase proliferating activity via L-type Ca 2ϩ channels in an NMDAR-dependent manner (Deisseroth et al, 2004).…”

Stress and adult neurogenesis

“…Stress increases glutamate release in the hippocampus (Lowry et al, 1993;Abraham et al, 1998), and several lines of evidence suggest that enhanced excitatory neurotransmission reduces cell proliferation. In both developing and adult animals, NMDA receptor activation reduces the number of new cells in the DG, while blockade of NMDA receptors or lesion of the entorhinal cortex, which provides the major excitatory input to the DG, has the opposite effect on cell proliferation (Cameron et al, 1995;Nacher et al, 2003;Okuyama et al, 2004). Moreover, blocking NMDA receptors prevents exogenous corticosterone from inhibiting cell proliferation (Cameron et al, 1998).…”