title: Homeostatic regulation of excitatory synapses on striatal medium spiny neurons expressing the D2 dopamine receptor.
abstract: Striatal medium spiny neurons (MSNs) are contacted by glutamatergic axon terminals originating from cortex, thalamus and other regions. The striatum is also innervated by dopaminergic (DAergic) terminals, some of which release glutamate as a co-transmitter. Despite evidence for functional DA release at birth in the striatum, the role of DA in the establishment of striatal circuitry is unclear. In light of recent work suggesting activity-dependent homeostatic regulation of glutamatergic terminals on MSNs expressing the D2 DA receptor (D2-MSNs), we used primary co-cultures to test the hypothesis that stimulation of DA and glutamate receptors regulates the homeostasis of glutamatergic synapses on MSNs. Co-culture of D2-MSNs with mesencephalic DA neurons or with cortical neurons produced an increase in spines and functional glutamate synapses expressing VGLUT2 or VGLUT1, respectively. The density of VGLUT2-positive terminals was reduced by the conditional knockout of this gene from DA neurons. In the presence of both mesencephalic and cortical neurons, the density of synapses reached the same total, compatible with the possibility of a homeostatic mechanism capping excitatory synaptic density. Blockade of D2 receptors increased the density of cortical and mesencephalic glutamatergic terminals, without changing MSN spine density or mEPSC frequency. Combined blockade of AMPA and NMDA glutamate receptors increased the density of cortical terminals and decreased that of mesencephalic VGLUT2-positive terminals, with no net change in total excitatory terminal density or in mEPSC frequency. These results suggest that DA and glutamate signaling regulate excitatory inputs to striatal D2-MSNs at both the pre- and postsynaptic level, under the influence of a homeostatic mechanism controlling functional output of the circuit.
authors.affiliation: Central Nervous System Research Group, Departments of Pharmacology and Neurosciences, Faculty of Medicine, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montreal, QC, H3C 3J7, Canada.
authors.forename: Dominic
authors.initials: D
authors.lastname: Thibault
authors.affiliation: Central Nervous System Research Group, Departments of Pharmacology and Neurosciences, Faculty of Medicine, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montreal, QC, H3C 3J7, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Giguère
authors.affiliation: Central Nervous System Research Group, Departments of Pharmacology and Neurosciences, Faculty of Medicine, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montreal, QC, H3C 3J7, Canada.
authors.forename: Fabien
authors.initials: F
authors.lastname: Loustalot
authors.affiliation: Central Nervous System Research Group, Departments of Pharmacology and Neurosciences, Faculty of Medicine, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montreal, QC, H3C 3J7, Canada.
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Bourque
authors.affiliation: Central Nervous System Research Group, Departments of Pharmacology and Neurosciences, Faculty of Medicine, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montreal, QC, H3C 3J7, Canada.
authors.forename: Charles
authors.initials: C
authors.lastname: Ducrot
authors.affiliation: Department of Psychiatry, Faculty of Medicine, McGill University, Douglas Mental Health University Institute, Montreal, QC, Canada.
authors.forename: Salah
authors.initials: S
authors.lastname: El Mestikawy
authors.affiliation: Central Nervous System Research Group, Departments of Pharmacology and Neurosciences, Faculty of Medicine, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montreal, QC, H3C 3J7, Canada. louis-eric.trudeau@umontreal.ca.
authors.forename: Louis-Éric
authors.initials: LÉ
authors.lastname: Trudeau
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000502:physiology; D059329:Cholinergic Neurons / Q000502:physiology; D018920:Coculture Techniques; D003342:Corpus Striatum / Q000378:metabolism / Q000502:physiology*; D049229:Dendritic Spines / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials; D018698:Glutamic Acid / Q000502:physiology; D006706:Homeostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D017729:Presynaptic Terminals / Q000502:physiology*; D018091:Receptors, AMPA / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism
chemical_list: D018091:Receptors, AMPA; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; C493477:Slc17a6 protein, mouse; C493465:Slc17a7 protein, mouse; D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2; D018698:Glutamic Acid
keywords: Dopamine; Glutamate; Homeostasis; Spines; Striatum; Terminals