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 excitatory axospinous synapses at the level of the dorsolateral striatum and motor cortex of adult xCT knockout (xCT-/-) and xCT wildtype (xCT+/+) mice. Our findings accommodate the hypothesis that system xc- negatively modulates neurotransmission, as morphological changes in the excitatory synapses in the dorsolateral striatum of xCT-/- mice reflect increased synaptic activity. In particular, we could observe 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, an increase in the length, thickness and area of the postsynaptic density, an increased occurrence of spinules, and an increase in the average area of synaptic vesicles. The ultrastructural changes observed in xCT deficient mice suggest the involvement of both presynaptic and postsynaptic forms of synaptic strength regulation via system xc-. In the future we would like to extend our findings on excitatory synapses in the motor cortex, as well as evaluate the expression of AMPA and NMDA receptor expression as a possible contributor to the increased size of the postsynaptic density in xCT deficient mice. Together, these 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.
|Title of host publication||Pre- and postsynaptic changes at excitatory synapses in xCT deficient mice|
|Publication status||Published - 2016|
|Event||46th Annual Meeting of the Society for Neuroscience - San Diego, United States|
Duration: 12 Nov 2016 → 16 Nov 2016
|Conference||46th Annual Meeting of the Society for Neuroscience|
|Period||12/11/16 → 16/11/16|
- System xc-