Activity- and age-dependent modulation of GABAergic neurotransmission by system A-mediated glutamine uptake.
GABAergic neurotransmission adapts to maintain normal brain function in a wide range of activity states through multiple mechanisms; pre-synaptic control of quantal size has only recently gained recognition as one of those mechanisms. GABA synthesis from glutamate is coupled with vesicular packaging, and therefore the supply of glutamate can affect inhibitory synaptic strength. Because System A transporters supply glutamine to neurons, where it is converted to glutamate, we hypothesized that regulation of the activity of these transporters could alter glutamine uptake and provide a mechanism to link supply to demand for neurotransmitter GABA. In immature and mature rat hippocampus, after a period of hyperexcitability, we observed a System A-dependent enhancement of inhibitory synaptic strength along with an increase in System A activity in synaptosomes under the same conditions. Under resting conditions, System A's contribution of glutamine to synaptic GABA diminished with age, correlating with reduced SNAT1/SAT1 expression and, even more so, with its activity on synaptic membranes. We conclude that System A activity is highly regulated, by depolarization and developmental cues, to dynamically modulate GABAergic transmission. Our evidence suggests that SNAT1/SAT1 is the transporter that plays a critical role in dynamically modulating inhibition in response to metabolic demands.
Brown
Molly N
MN
Department of Neurology, Vanderbilt University, Nashville, Tennessee 37232-8552, USA.
Mathews
Gregory C
GC
D000375:Aging / Q000378:metabolism / Q000502:physiology*; D026924:Amino Acid Transport System A / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000254:growth & development / Q000502:physiology*; D009433:Neural Inhibition / Q000502:physiology; D018377:Neurotransmitter Agents / Q000502:physiology*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis / Q000502:physiology*
D026924:Amino Acid Transport System A; D002352:Carrier Proteins; D018377:Neurotransmitter Agents; C486716:Slc38a1 protein, rat; C037853:glutamine transport proteins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid