ACTIVITY-DEPENDENT EXPRESSION OF PARATHYROID HORMONE-RELATED PROTEIN (PTHRP) IN RAT CEREBELLAR GRANULE NEURONS - REQUIREMENT OF PTHRP FOR THE ACTIVITY-DEPENDENT SURVIVAL OF GRANULE NEURONS

To identify genes whose expression is neuronal activity-dependent, we used an mRNA differential display technique and discovered that parath yroid hormone-related protein (PTHrP) is expressed in an activity-depe ndent manner in primary cultures of rat cerebellar granule neurons. PT HrP mRNA was expressed as early as 1 h by the addition of KCl to a fin al concentration of 25 mM to the culture medium. This expression was i nduced by Ca2+ influx through voltage-dependent L-type Ca2+ channels a nd regulated at the transcriptional step. PTHrP mRNA was persistently expressed before and after the time of commitment of granule neurons t o apoptosis when they are cultured in the presence of 25 mM KCl or bot h 150 mu M N-methyl-D-aspartic acid and 15 mM KCl, both of which promo te the survival of these neurons, PTHrP was rapidly secreted into the culture medium in a depolarization-dependent manner. Parathyroid hormo ne/PTHrP receptor mRNA was also expressed in the primary cultures, and its expression was up-regulated by KCl and/or N-methyl-D-aspartic aci d. The addition of anti-PTHrP antiserum to the culture medium resulted in a reduction of the activity-dependent survival of the granule neur ons, These results suggest that PTHrP is involved in an autocrine loop and required for the survival of granule neurons.