Chronic activation of the D2 autoreceptor inhibits both glutamate and dopamine synapse formation and alters the intrinsic properties of mesencephalic dopamine neurons in vitro.
Dysfunctional dopamine (DA)-mediated signaling is implicated in several diseases including Parkinson's disease, schizophrenia and attention deficit and hyperactivity disorder. Chronic treatment with DA receptor agonists or antagonists is often used in pharmacotherapy, but the consequences of these treatments on DA neuron function are unclear. It was recently demonstrated that chronic D2 autoreceptor (D2R) activation in DA neurons decreases DA release and inhibits synapse formation. Given that DA neurons can establish synapses that release glutamate in addition to DA, we evaluated the synapse specificity of the functional and structural plasticity induced by chronic D2R activation. We show that chronic activation of the D2R with quinpirole in vitro caused a parallel decrease in the number of dopaminergic and glutamatergic axon terminals. The capacity of DA neurons to synthesize DA was not altered, as indicated by the lack of change in protein kinase A-mediated Ser(40) phosphorylation of tyrosine hydroxylase. However, the spontaneous firing rate of DA neurons was decreased and was associated with altered intrinsic properties as revealed by a prolonged latency to first spike after release from hyperpolarization. Moreover, D2R function was decreased after its chronic activation. Our results demonstrate that chronic activation of the D2R induces a complex neuronal reorganization involving the inhibition of both DA and glutamate synapse formation and an alteration in electrical activity, but not in DA synthesis. A better understanding of D2R-induced morphological and functional long-term plasticity may lead to improved pharmacotherapy of DA-related neurological and psychiatric disorders.
Fasano
C
C
Department of Pharmacology, Groupe de Recherche sur le Système Nerveux Central, Faculty of Medicine, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, QC H3C 3J7, Canada.
Kortleven
C
C
Trudeau
L-E
LE
D000818:Animals; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D008636:Mesencephalon / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D019257:Quinpirole / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D018698:Glutamic Acid; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine