Genetic evidence for the requirement of adenylyl cyclase 1 in synaptic scaling of forebrain cortical neurons.
Homeostatic plasticity is important to stabilize the activity level of neuronal circuits. Molecular mechanisms underlying neuronal homeostatic plasticity in response to activity deprivation are not completely understood. We found that prolonged alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blockade by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) resulted in larger, faster miniature excitatory postsynaptic current (mEPSC) events with enhanced frequency in cultured forebrain cortical neurons. Furthermore, GluR1 protein level and CREB-dependent transcription were up-regulated. Blockade of L-type Ca(2+) channels but not kainate receptors produced similar effects to the AMPA receptor blockade. Genetic deletion of AC1 (adenylyl cyclase 1), but not AC8, a key neuronal adenylyl cyclase, significantly reduced inactivity-induced GluR1 changes. Our results indicate the synthesis of homomeric GluR1 AMPA receptors and their possible insertion into synapses due to synaptic inactivity in the cortex. AC1 plays a subtype selective role in this process by coupling signals from L-type Ca(2+) channels to downstream signalling pathways.
Gong
Bo
B
Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada.
Wang
Hansen
H
Gu
Steven
S
Heximer
Scott P
SP
Zhuo
Min
M
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D020746:Calcium Channels, L-Type / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology* / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology; D003627:Data Interpretation, Statistical; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D017930:Genes, Reporter / Q000235:genetics; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000201:enzymology* / Q000502:physiology*; D018408:Patch-Clamp Techniques; D016548:Prosencephalon / Q000201:enzymology / Q000502:physiology; D018091:Receptors, AMPA / Q000187:drug effects; D018092:Kainic Acid Receptors / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000201:enzymology* / Q000502:physiology*
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000262:Adenylyl Cyclases; D020746:Calcium Channels, L-Type; D000242:Cyclic AMP; D018691:Excitatory Amino Acid Antagonists; D008156:Luciferases; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; C106670:adenylyl cyclase 1; C118292:adenylyl cyclase 8