Transcriptional regulation of polysialylated neural cell adhesion molecule expression by NMDA receptor activation in retinoic acid-differentiated SH-SY5Y neuroblastoma cultures.

NMDA receptors exhibit a dichotomy of signaling with excessive stimulation leading to neuronal damage that occurs during neurodegenerative disorders, whereas the normal burst of activity results in plastic responses with the expression of molecular substrates of long-term plasticity, growth and survival. Control of polysialylated neural cell adhesion molecule (PSA-NCAM) expression by NMDA receptor activation has been described in several systems, suggesting a functional link between these two proteins. The coordinated induction of several different transcription factors initiated by NMDA receptor stimulation may be a key mechanism in the orchestration of specific target gene expression that underlies various aspects of CNS function, including plastic responses. We report here the transcriptional regulation of PSA-NCAM expression by subtoxic dose of NMDA in retinoic acid-differentiated SH-SY5Y cell cultures. SH-SY5Y cell cultures differentiated with retinoic acid (10 microM) were exposed to NMDA (100 microM) or to antagonist MK-801 (200 nM) prior to treatment with NMDA and cells were harvested after 24 h of treatment to study the expression of PSA-NCAM, nuclear factor kappaB (NF-kappaB) and activator protein-1 (AP-1) by Western blotting and dual immunocytofluorescence and expression of polysialyltransferase (PST) mRNA by fluorescent in situ hybridization (FISH). We observed the induction of transcription factors NF-kappaB and AP-1 along with PSA-NCAM expression in response to NMDA receptor activation. Also, PSA-NCAM regulation in response to NMDA receptor activity was shown to be transcriptionally controlled, as seen by temporal and spatial changes observed in the expression of PST mRNA in NMDA-treated SH-SY5Y cell cultures. This raises the interesting possibility that NF-kappaB and AP-1 expression is involved in propagating the signals of NMDA receptor activity that leads to downstream strengthening of long-term plasticity changes in differentiated SH-SY5Y neuroblastoma cell cultures. Thus understanding the regulation of PSA-NCAM expression by NMDA receptor-mediated activity may represent a fundamental prerequisite for the development of therapies in order to maintain neuronal plasticity throughout life and functional recovery after brain damage.