"As long as our brain is a mystery, the universe, the reflection of the structure of the brain will also be a mystery.”
― Santiago Ramón y Cajal
Synapses in the mammalian brain are exposed to two biologically active pools of glutamate: 1) transient synaptic glutamate resulting from neuronal vesicular release and 2) ambient nonsynaptic glutamate released from both neurons and glia through a variety of molecular mechanisms. While the role of synaptic glutamate has been extensively studied, much of the function of nonsynaptic glutamate remains unknown. Several lines of evidence have shown that changes in nonsynaptic glutamate are linked to developmental, physiological, and behavioral defects in mammals. Approximately 60% of extracellular glutamate in the mouse hippocampus is released by the xCT transporter, a cystine-glutamate antiporter which is highly expressed and active on astrocytes surrounding CA1 pyramidal neurons.
In my lab, we have obtained a line of mutant mice that lack a functional xCT transporter (xCT-/-). These knockout mice show both enhanced synaptic strength and increased AMPA receptor abundance at hippocampal CA3-CA1 synapses. Additionally, mutant xCT-/- miniature excitatory post-synaptic potentials (mEPSCs) are phenocopied by incubating control slices in glutamate-free solution. This evidence suggests that xCT-derived extracellular glutamate may be suppressing synapse strength in the hippocampus. My research aims to determine the mechanism by which the xCT transporter suppresses synapse strength in the mammalian hippocampus, and how xCT function is linked to abnormal brain states.