Convulsant Doses of a Dopamine D1 Receptor Agonist Result in Erk-Dependent Increases in Zif268 and Arc/Arg3.1 Expression in Mouse Dentate Gyrus

Abstract

Activation of dopamine D1 receptors (D1Rs) has been shown to induce epileptiform activity. We studied the molecular changes occurring in the hippocampus in response to the administration of the D1-type receptor agonist, SKF 81297. SKF 81297 at 2.5 and 5.0 mg/kg induced behavioural seizures. Electrophysiological recordings in the dentate gyrus revealed the presence of epileptiform discharges peaking at 30–45 min post-injection and declining by 60 min. Seizures were prevented by the D1-type receptor antagonist, SCH 23390, or the cannabinoid CB1 receptor agonist, CP 55,940. The effect of SKF 81297 was accompanied by increased phosphorylation of the extracellular signal-regulated protein kinases 1 and 2 (ERK), in the granule cells of the dentate gyrus. This effect was also observed in response to administration of other D1-type receptor agonists, such as SKF83822 and SKF83959. In addition, SKF 81297 increased the phosphorylation of the ribosomal protein S6 and histone H3, two downstream targets of ERK. These effects were prevented by genetic inactivation of D1Rs, or by pharmacological inhibition of ERK. SKF 81297 was also able to enhance the levels of Zif268 and Arc/Arg3.1, two immediate early genes involved in transcriptional regulation and synaptic plasticity. These changes may be involved in forms of activity-dependent plasticity linked to the manifestation of seizures and to the ability of dopamine to affect learning and memory.

Regulation of the ERK pathway in the dentate gyrus by in vivo dopamine D1 receptor stimulation requires glutamatergic transmission

“…We previously showed that SKF81297 increased the state of phosphorylation of rpS6 at the dual site Ser235/236 through a partial ERK-dependent mechanism (Gangarossa et al, 2011). We therefore examined whether mGluR1 and mGluR5 receptors were involved in the regulation of rpS6 phosphorylation triggered by SKF81297 (Fig.…”

“…1) (Gangarossa et al, 2011). Increasing evidences suggest that D1R-dependent ERK activation requires glutamatergic transmission (Kaphzan et al, 2006;Pascoli et al, 2011;Sarantis et al, 2009).…”

“…In addition, several reports highlight that modulation of D1Rs could impact on the seizure threshold. Indeed, the administration of D1R-like agonist induces seizures (Gangarossa et al, 2011;O'Sullivan et al, 2008) and decrease seizure threshold in the pilocarpine model (al-Tajir et al, 1990;Alam and Starr, 1992). Moreover, D1R neuron-ablated mice displayed spontaneous stereotyped seizures, which have been associated to cell loss, astrogliosis and microgliosis in the dentate gyrus (Gantois et al, 2007).…”

“…In the granule cells of the dentate gyrus, SKF81297 triggered a rapid and transient ERK-dependent phosphorylation of histone H3, which has been associated with the upregulation of two plasticity-associated genes, Zif268 and Arc/Arg3.1 (Gangarossa et al, 2011). Although, these effects are mediated by D1Rs stimulation, whether glutamate could contribute to this regulation has never been investigated.…”

“…SKF81297 is also able to increase the phosphorylation state of the component of the small 40S ribosomal subunit, the ribosomal protein S6 (rpS6) at the Ser235/236 site (Gangarossa et al, 2011). Phosphorylation of rpS6 on this residue is known to correlate with an increase in translation of specific mRNAs that contain an oligopyrimidine tract in their 5 0 UTR regions (Ruvinsky and Meyuhas, 2006).…”