EAAT1-dependent Transcriptional Control depends on the Substrate Translocation Process

Abstract

Glutamate, the major excitatory neurotransmitter in the vertebrate brain, is removed from the synaptic cleft by a family of sodium-dependent transporters expressed in neurons and glial cells. The bulk of glutamate uptake activity occurs in glial cells through the sodium-dependent glutamate/aspartate transporter (EAAT1/GLAST) and glutamate transporter 1 (EAAT2/GLT-1). EAAT1/GLAST is the predominant transporter within the cerebellum. It is highly enriched in Bergmann glial cells that span the cerebellar cortex and wrap the most abundant glutamatergic synapses in the central nervous system, the synapse formed by the parallel fibers and the Purkinje cells. In the past years, it has become evident that Bergmann glial cells are involved in glutamatergic transmission. Glutamate transporters are tightly regulated due to their essential role in tripartite synapses. Glutamate regulates EAAT1/GLAST function and gene expression in a receptor-dependent and receptor-independent manner. Through the use of the non-metabolizable EAAT1/GLAST ligand, D-Aspartate, and the well-established chick cerebellar Bergmann glia primary culture, in this contribution, we demonstrate that EAAT1/GLAST down-regulates its expression and function at the transcriptional level through the activation of a signaling pathway that includes the phosphatidyl inositol 3 kinase (PI3K), the Ca 2+ /diacylglycerol dependent protein kinase PKC and the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB). These results favor the notion of an activity-dependent fine-tuning of glutamate recycling and its synaptic transactions through glial cells. Summary statement EAAT1/GLAST down-regulates its expression and function at the transcriptional level by activating a signaling pathway that includes PI3K, PKC and NF-κB, favoring the notion of an activity-dependent fine-tuning of glutamate recycling and its synaptic transactions through glial cells.