The vesicular glutamate transporter VGLUT3 synergizes striatal acetylcholine tone.
Three subtypes of vesicular transporters accumulate glutamate into synaptic vesicles to promote its vesicular release. One of the subtypes, VGLUT3, is expressed in neurons, including cholinergic striatal interneurons, that are known to release other classical transmitters. Here we showed that disruption of the Slc17a8 gene (also known as Vglut3) caused an unexpected hypocholinergic striatal phenotype. Vglut3(-/-) mice were more responsive to cocaine and less prone to haloperidol-induced catalepsy than wild-type littermates, and acetylcholine release was decreased in striatum slices lacking VGLUT3. These phenotypes were associated with a colocalization of VGLUT3 and the vesicular acetylcholine transporter (VAChT) in striatal synaptic vesicles and the loss of a synergistic effect of glutamate on vesicular acetylcholine uptake. We propose that this vesicular synergy between two transmitters is the result of the unbalanced bioenergetics of VAChT, which requires anion co-entry for continuing vesicular filling. Our study reveals a previously unknown effect of glutamate on cholinergic synapses with potential functional and pharmacological implications.
Gras
Christelle
C
Institut National de la Santé et de la Recherche Médicale, U513, Université Pierre et Marie Curie, 9 quai Saint Bernard, 75005 Paris, France.
Amilhon
Bénédicte
B
Lepicard
Eve M
EM
Poirel
Odile
O
Vinatier
Jacqueline
J
Herbin
Marc
M
Dumas
Sylvie
S
Tzavara
Eleni T
ET
Wade
Mark R
MR
Nomikos
George G
GG
Hanoun
Naïma
N
Saurini
Françoise
F
Kemel
Marie-Louise
ML
Gasnier
Bruno
B
Giros
Bruno
B
El Mestikawy
Salah
S
D000109:Acetylcholine / Q000096:biosynthesis / Q000378:metabolism*; D026922:Amino Acid Transport Systems, Acidic / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D015536:Down-Regulation / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism*; D007395:Interneurons / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009924:Organ Culture Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics*; D013572:Synaptic Vesicles / Q000378:metabolism; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism
D000109:Acetylcholine; D026922:Amino Acid Transport Systems, Acidic; D014150:Antipsychotic Agents; D018765:Dopamine Uptake Inhibitors; D018698:Glutamic Acid; D050494:Vesicular Acetylcholine Transport Proteins; C493460:Slc18a3 protein, mouse; C504941:Slc17a8 protein, mouse