Homeostatic regulation of excitatory synapses on striatal medium spiny neurons expressing the D2 dopamine receptor.
Brain Struct Funct. 2015-03-18; 221(4): 2093-2107
DOI: 10.1007/s00429-015-1029-4
Read on PubMed
Thibault D(1), Giguère N(1), Loustalot F(1), Bourque MJ(1), Ducrot C(1), El Mestikawy S(2), Trudeau LÉ(3).
Author information:
(1)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.
(2)Department of Psychiatry, Faculty of Medicine, McGill University, Douglas
Mental Health University Institute, Montreal, QC, Canada.
(3)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. .
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.