Cerebral Cortex Advance Access originally published online on October 1, 2008
Cerebral Cortex 2009 19(5):1092-1106; doi:10.1093/cercor/bhn151
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System A Transporter SAT2 Mediates Replenishment of Dendritic Glutamate Pools Controlling Retrograde Signaling by Glutamate
1 The Biotechnology Centre of Oslo, 2 The Centre for Molecular Biology and Neuroscience, and Department of Anatomy, Institute for Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway, 3 Departments of Neuroscience, 4 Medical Biochemistry and Biophysics, 5 Physiology and Pharmacology, Karolinska Institutet, SE-17177 Stockholm, Sweden, 6 Department of Psychology, Life Science North Bldg., Rm 381, University of Arizona, Tucson, AZ 85724, USA, 7 Institute of Medical Sciences, College of Life Sciences & Medicine, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, UK
Address correspondence to Farrukh A. Chaudhry, MD, PhD, The Biotechnology Centre of Oslo, University of Oslo, P.O. Box 1125 Blindern, N-0317 Oslo, Norway. Email: f.a.chaudhry{at}biotek.uio.no.
Glutamate mediates several modes of neurotransmission in the central nervous system including recently discovered retrograde signaling from neuronal dendrites. We have previously identified the system N transporter SN1 as being responsible for glutamine efflux from astroglia and proposed a system A transporter (SAT) in subsequent transport of glutamine into neurons for neurotransmitter regeneration. Here, we demonstrate that SAT2 expression is primarily confined to glutamatergic neurons in many brain regions with SAT2 being predominantly targeted to the somatodendritic compartments in these neurons. SAT2 containing dendrites accumulate high levels of glutamine. Upon electrical stimulation in vivo and depolarization in vitro, glutamine is readily converted to glutamate in activated dendritic subsegments, suggesting that glutamine sustains release of the excitatory neurotransmitter via exocytosis from dendrites. The system A inhibitor MeAIB (
-methylamino-iso-butyric acid) reduces neuronal uptake of glutamine with concomitant reduction in intracellular glutamate concentrations, indicating that SAT2-mediated glutamine uptake can be a prerequisite for the formation of glutamate. Furthermore, MeAIB inhibited retrograde signaling from pyramidal cells in layer 2/3 of the neocortex by suppressing inhibitory inputs from fast-spiking interneurons. In summary, we demonstrate that SAT2 maintains a key metabolic glutamine/glutamate balance underpinning retrograde signaling by dendritic release of the neurotransmitter glutamate.
Key Words: amino acid • glutamate–glutamine cycle • neurotransmitter release • SLC38 • SNAT2 • synaptic plasticity
Monica Jenstad, Abrar Z. Quazi, and Misha Zilberter have contributed equally to this work.