title: Non-cell-autonomous mechanism of activity-dependent neurotransmitter switching.
abstract: Activity-dependent neurotransmitter switching engages genetic programs regulating transmitter synthesis, but the mechanism by which activity is transduced is unknown. We suppressed activity in single neurons in the embryonic spinal cord to determine whether glutamate-gamma-aminobutyric acid (GABA) switching is cell autonomous. Transmitter respecification did not occur, suggesting that it is homeostatically regulated by the level of activity in surrounding neurons. Graded increase in the number of silenced neurons in cultures led to graded decrease in the number of neurons expressing GABA, supporting non-cell-autonomous transmitter switching. We found that brain-derived neurotrophic factor (BDNF) is expressed in the spinal cord during the period of transmitter respecification and that spike activity causes release of BDNF. Activation of TrkB receptors triggers a signaling cascade involving JNK-mediated activation of cJun that regulates tlx3, a glutamate/GABA selector gene, accounting for calcium-spike BDNF-dependent transmitter switching. Our findings identify a molecular mechanism for activity-dependent respecification of neurotransmitter phenotype in developing spinal neurons.
authors.affiliation: Neurobiology Section, Division of Biological Sciences and Center for Neural Circuits and Behavior, Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA 92093-0357, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Guemez-Gamboa
authors.affiliation: Neurobiology Section, Division of Biological Sciences and Center for Neural Circuits and Behavior, Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA 92093-0357, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Neurobiology Section, Division of Biological Sciences and Center for Neural Circuits and Behavior, Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA 92093-0357, USA.
authors.forename: Da
authors.initials: D
authors.lastname: Meng
authors.affiliation: Neurobiology Section, Division of Biological Sciences and Center for Neural Circuits and Behavior, Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA 92093-0357, USA. Electronic address: nspitzer@ucsd.edu.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Spitzer
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction; D013116:Spinal Cord / Q000196:embryology* / Q000378:metabolism; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016755:Proto-Oncogene Proteins c-jun; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D048031:JNK Mitogen-Activated Protein Kinases; D002118:Calcium