SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons.
Silent synapses, or excitatory synapses that lack functional alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), are thought to be critical for regulation of neuronal circuits and synaptic plasticity. Here, we report that SynGAP, an excitatory synapse-specific RasGAP, regulates AMPAR trafficking, silent synapse number, and excitatory synaptic transmission in hippocampal and cortical cultured neurons. Overexpression of SynGAP in neurons results in a remarkable depression of AMPAR-mediated miniature excitatory postsynaptic currents, a significant reduction in synaptic AMPAR surface expression, and a decrease in the insertion of AMPARs into the plasma membrane. This change is specific for AMPARs because no change is observed in synaptic NMDA receptor expression or total synapse density. In contrast to these results, synaptic transmission is increased in neurons from SynGAP knockout mice as well as in neuronal cultures treated with SynGAP small interfering RNA. In addition, activation of the extracellular signal-regulated kinase, ERK, is significantly decreased in SynGAP-overexpressing neurons, whereas P38 mitogen-activated protein kinase (MAPK) signaling is potentiated. Furthermore, ERK activation is up-regulated in neurons from SynGAP knockout mice, whereas P38 MAPK function is depressed. Taken together, these data suggest that SynGAP plays a critical role in the regulation of neuronal MAPK signaling, AMPAR membrane trafficking, and excitatory synaptic transmission.
Department of Neuroscience and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Gavin
G
Rumbaugh
J Paige
JP
Adams
Jee H
JH
Kim
Richard L
RL
Huganir
D000818:Animals; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D009474:Neurons / Q000737:chemistry / Q000201:enzymology / Q000502:physiology*; D021381:Protein Transport; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism / Q000502:physiology; D009435:Synaptic Transmission; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*
D018091:Receptors, AMPA; C484512:Syngap1 protein, mouse; D020703:ras GTPase-Activating Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases