Single-cell optogenetic excitation drives homeostatic synaptic depression.
Homeostatic processes have been proposed to explain the discrepancy between the dynamics of synaptic plasticity and the stability of brain function. Forms of synaptic plasticity such as long-term potentiation alter synaptic activity in a synapse- and cell-specific fashion. Although network-wide excitation triggers compensatory homeostatic changes, it is unknown whether neurons initiate homeostatic synaptic changes in response to cell-autonomous increases in excitation. Here we employ optogenetic tools to cell-autonomously excite CA1 pyramidal neurons and find that a compensatory postsynaptic depression of both AMPAR and NMDAR function results. Elevated calcium influx through L-type calcium channels leads to activation of a pathway involving CaM kinase kinase and CaM kinase 4 that induces synaptic depression of AMPAR and NMDAR responses. The synaptic depression of AMPARs but not of NMDARs requires protein synthesis and the GluA2 AMPAR subunit, indicating that downstream of CaM kinase activation divergent pathways regulate homeostatic AMPAR and NMDAR depression.
Departments of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA.
Carleton P
CP
Goold
Roger A
RA
Nicoll
D000818:Animals; D001921:Brain / Q000502:physiology; D056547:CA1 Region, Hippocampal / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000502:physiology; D020013:Calcium Signaling / Q000235:genetics / Q000502:physiology; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D000075402:Channelrhodopsins; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006706:Homeostasis / Q000235:genetics* / Q000502:physiology*; D066298:In Vitro Techniques; D051379:Mice; D009473:Neuronal Plasticity / Q000502:physiology; D018408:Patch-Clamp Techniques; D010775:Photic Stimulation; D014176:Protein Biosynthesis / Q000502:physiology; D017966:Pyramidal Cells / Q000502:physiology; D051381:Rats; D018091:Receptors, AMPA / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D013569:Synapses / Q000502:physiology*
D020746:Calcium Channels, L-Type; D000075402:Channelrhodopsins; D004791:Enzyme Inhibitors; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4