AMPA receptors regulate transcription of the plasticity-related immediate-early gene Arc.
Learning and memory depend critically on long-term synaptic plasticity, which requires neuronal gene expression. In the prevailing view, AMPA receptors mediate fast excitatory synaptic transmission and effect short-term plasticity, but they do not directly regulate neuronal gene expression. By studying regulation of Arc, a gene required for long-term plasticity, we uncovered a new role for AMPA receptors in neuronal gene expression. Spontaneous synaptic activity or activity induced by brain-derived neurotrophic factor (BDNF) elicited Arc expression in cultures of rat cortical neurons and in organotypic brain slices. Notably, inhibiting AMPA receptors strongly potentiated activity-dependent Arc expression. We found that AMPA receptors negatively regulate Arc transcription, but not translation or stability, through a mechanism involving a pertussis toxin-sensitive G protein. These results provide insights into the activity-dependent mechanisms of Arc expression and suggest that, in addition to effecting short-term plasticity, AMPA receptors regulate genes involved in long-term plasticity.
Rao
Vikram R
VR
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.
Pintchovski
Sean A
SA
Chin
Jeannie
J
Peebles
Carol L
CL
Mitra
Siddhartha
S
Finkbeiner
Steven
S
D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D066298:In Vitro Techniques; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D051381:Rats; D018091:Receptors, AMPA / Q000502:physiology*; D014162:Transfection / Q000379:methods
D019208:Brain-Derived Neurotrophic Factor; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; C092069:activity regulated cytoskeletal-associated protein; D002118:Calcium; D001640:Bicuculline