The cystine/glutamate antiporter system xc- as modulator of corticostriatal neurotransmission
Olaya
Lara1*,
Eduard
Bentea1,
Agnes
Villers2,
Cynthia
Moore3,
Adam
Funk4,
Sinead
O'Donovan4,
Lise
Verbruggen1,
Laura
De Pauw1,
Erica
Depasquale5,
Madeline
Churchill3,
Hideyo
Sato6,
Laurence
Ris2,
Charles
K.
Meshul7,
Robert
McCullumsmith4 and
Ann
Massie1
-
1
Vrije University Brussel, Belgium
-
2
University of Mons, Belgium
-
3
Portland VA Research Foundation, United States
-
4
University of Toledo, United States
-
5
University of Cincinnati, United States
-
6
Niigata University, Japan
-
7
Oregon Health & Science University, United States
The cystine/glutamate antiporter system xc-, with xCT as specific subunit, exchanges intracellular glutamate for extracellular cystine. It is highly expressed in the central nervous system, mainly on astrocytes, and has been shown to be the major source of extracellular glutamate in various regions of the brain, such as the striatum and hippocampus. This extrasynaptically released glutamate can affect synaptic neurotransmission. As the physiological function of system xc- in the central nervous system remains poorly understood, we studied how system xc- regulates transmission at corticostriatal synapses, one of the two major types of striatal excitatory synapses. Electrophysiological recordings identified a significant decrease in the amplitude of striatal field excitatory postsynaptic potentials in mice genetically lacking xCT (xCT-/- mice) following stimulation of corticostriatal fibers. Further, using electron microscopy, we observed depletion of glutamate immunogold labeling from corticostriatal terminals and their corresponding dendritic spines in xCT-/- mice. Genetic deletion of xCT did not, however, affect the morphology of corticostriatal synapses, the density of cortical innervation or the density of dendritic spines in the striatum. Proteomic analysis revealed decreased expression of a wide range of proteins involved in regulating presynaptic neurotransmitter release in the striatum of xCT-/- mice, including synaptophysin, VGLUT1, and members of the synapsin, septin, and syntaxin families. In addition, kinome profiling identified changes in striatal serine/threonine kinase activity, highlighting ERK signaling as a possible node of kinase dysregulation in xCT-/- mice. Finally, we evaluated the effect of the disturbed corticostriatal communication on the behavioral phenotype of the xCT-/- mice. In the marble burying test, a paradigm sensitive to changes in corticostriatal function, we measured a significant increase in repetitive digging behavior in xCT-/- mice. Whereas spontaneous grooming behavior was not affected by genetic deletion of xCT, we have preliminary findings from the reciprocal interaction and three-chamber test, suggesting aberrant social behavior. Together, our results identify system xc- as a modulator of corticostriatal synaptic transmission that may be relevant to neuropsychiatric disorders characterized by corticostriatal dysfunction and repetitive behavior, such as obsessive-compulsive behavior and autism.
Acknowledgements
The authors acknowledge the Fund for Scientific Research Flanders (FWO), the Queen Elisabeth Medical Foundation (G.S.K.E.) and the Vrije Universiteit Brussel (Strategic Research Program, grant SRP40) for financial support.
Keywords:
System xc-,
Corticostriatal neurotransmission,
Kinomics,
Proteomics,
Medium spiny neurons,
Social Behavior
Conference:
13th National Congress of the Belgian Society for Neuroscience , Brussels, Belgium, 24 May - 24 May, 2019.
Presentation Type:
Poster presentation
Topic:
Cellular/Molecular Neuroscience
Citation:
Lara
O,
Bentea
E,
Villers
A,
Moore
C,
Funk
A,
O'Donovan
S,
Verbruggen
L,
De Pauw
L,
Depasquale
E,
Churchill
M,
Sato
H,
Ris
L,
Meshul
CK,
McCullumsmith
R and
Massie
A
(2019). The cystine/glutamate antiporter system xc- as modulator of corticostriatal neurotransmission.
Front. Neurosci.
Conference Abstract:
13th National Congress of the Belgian Society for Neuroscience .
doi: 10.3389/conf.fnins.2019.96.00050
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Received:
24 Apr 2019;
Published Online:
27 Sep 2019.
*
Correspondence:
Mx. Olaya Lara, Vrije University Brussel, Brussels, Belgium, olaya.lara@vub.be