Chronic activation of the D2 dopamine autoreceptor inhibits synaptogenesis in mesencephalic dopaminergic neurons in vitro

Abstract

Chronic blockade or activation of dopamine receptors is critical for the pharmacological treatment of diseases like schizophrenia, Parkinson's or attention deficit and hyperactivity disorder. However, the long-term impact of such treatments on dopamine neurons is unclear. Chronic blockade of the dopamine D2 receptor in vivo triggers an increase in the axonal arborization of dopamine neurons [European Journal of Neuroscience, 2002, 16, 787-794]. However, the specific involvement of presynaptic (autoreceptors) vs. postsynaptic D2 receptors as well as the molecular mechanisms involved have not been determined. Here, we examined the role of D2 autoreceptors in regulating the ability of mouse dopamine neurons to establish axon terminals. Chronic activation of this receptor with quinpirole, a specific agonist, decreased the number of axon terminals established by isolated dopamine neurons. This effect was accompanied by a decrease in dopamine release and was mediated through inhibition of protein kinase A. The decrease in axon terminal number induced by D2 receptor activation was also occluded when the mammalian Target of Rapamycin pathway of mRNA translation was blocked. Our results suggest that chronic activation of the D2 autoreceptor inhibits synaptogenesis by mesencephalic dopamine neurons through translational regulation of the synthesis of proteins required for synapse formation. This study provides a better understanding of the impact of long-term pharmacological interventions acting through the D2 receptor.

Chronic activation of the D2 autoreceptor inhibits both glutamate and dopamine synapse formation and alters the intrinsic properties of mesencephalic dopamine neurons in vitro

“…S1A and B) or as microcultures in which single isolated DA neurons can be studied (Fig. S1C and D) (Fasano et al. , 2008a,b).…”

“…, 2003). Using an in vitro microculture model in which the axon terminals of single DA neurons can be examined, we recently demonstrated that chronic activation of the D2R in DA neurons inhibits synapse formation and decreases DA release without inhibiting the expression of tyrosine hydroxylase (TH), the rate‐limiting enzyme of DA synthesis (Fasano et al. , 2008a).…”

“…, 2008) in a subset of their axon terminals. Because prior work (Fasano et al. , 2008a) quantified synapse number based on the expression of the ubiquitous synaptic vesicle protein 2 (SV2) (Yao & Bajjalieh, 2008; Chang & Sudhof, 2009), the synapse‐specificity of D2R‐mediated inhibition of synaptogenesis in DA neurons remains undetermined.…”

Assessing the molecular genetics of the development of executive attention in children: focus on genetic pathways related to the anterior cingulate cortex and dopamine

“…Within the developing brain, DA participates in cellular changes such as myelination, synaptogenesis and pruning (W. Shen et al, 2007; C. Fasano et al, 2008; Y.…”

Découvertes récentes sur la fonction et la plasticité des voies dopaminergiques du cerveau

“…Des travaux récents de notre groupe ont abouti à la mise au point d'un modèle in vitro d'inhibition de la formation de terminaisons axonales déclenchée par la stimulation chronique de l'autorécepteur D2 (Figure 1, partie 2). Nous avons ainsi pu démontrer que ce phénomène requiert une inhibition de la PKA et de la voie mTOR (mammalian target of rapamycin)/ p70-S6 kinase, une voie de signalisation participant à la régulation de la traduction des ARN messagers [13]. D'autres découvertes particulièrement intéressantes ont également été faites au cours des dernières années, montrant qu'un déséquilibre du système dopaminergique provoque aussi des changements structuraux au niveau post-synaptique.…”