System xc- is a plasma membrane amino acid antiporter, of mainly glial origin, that couples the import of cystine with the export of glutamate. System xc- (specific subunit xCT) contributes substantially to ambient extracellular glutamate levels in various regions of the brain, including the striatum and hippocampus. Despite the fact that system xc- is highly expressed in the brain and is a proposed therapeutic target for various neurological disorders, including Parkinson’s disease, Alzheimer’s disease, multiple sclerosis and epilepsy, its function under physiological conditions in the central nervous system remains poorly understood. By acting as a source of glial extrasynaptic glutamate, system xc- might modulate synaptic transmission as a mechanism of neuro-glial communication. Previous electrophysiological findings indicate that system xc- delivered glutamate can inhibit excitatory synaptic neurotransmission in the cortico-accumbens pathway (Moran et al. J Neurosci. 2005; 25:6389-93) and at hippocampal CA3-CA1 synapses (Williams et al. J Neurosci. 2014; 34:16093-102). In order to gain further insight into the proposed function of system xc- as modulator of synaptic transmission, we carried out single section electron microscopy analyses of cortico-striatal excitatory synapses in adult xCT knockout (xCT-/-) and xCT wildtype (xCT+/+) mice. Our preliminary findings reveal depletion of glutamate immunogold labeling from presynaptic terminals of xCT-/- mice, an increase in the head diameter and area of spines contacted by asymmetric synapses, enlargement of the postsynaptic density and an increased occurrence of spinules, post-synaptic elements of high efficacy. These synaptic changes occurred in the absence of differences in the total density of cortico-striatal synapses or dendritic spines in the dorsolateral striatum of xCT-/- vs. xCT+/+ mice. Our results suggest the involvement of both presynaptic and postsynaptic forms of synaptic strength regulation via system xc-. Whether the structural changes we observed indicate a global increase in cortico-striatal transmission in xCT-/- mice, or conversely, represent forms of synaptic compensation, is being addressed by electrophysiological measures of excitatory post-synaptic currents in xCT-/- mice after cortical stimulation. Together, our findings shed new light on the re-organization of the glutamatergic system after genetic deletion of system xc-, and confirm the involvement of this antiporter in the control of synaptic strength in vivo.
|Other||12th National Congress of the Belgian Society for Neuroscience|
|Period||22/05/17 → …|
- corticostriatal pathway
- Electron microscopy
- Synaptic Transmission