Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number.
In the mammalian nervous system, neuronal activity regulates the strength and number of synapses formed. The genetic program that coordinates this process is poorly understood. We show that myocyte enhancer factor 2 (MEF2) transcription factors suppressed excitatory synapse number in a neuronal activity- and calcineurin-dependent manner as hippocampal neurons formed synapses. In response to increased neuronal activity, calcium influx into neurons induced the activation of the calcium/calmodulin-regulated phosphatase calcineurin, which dephosphorylated and activated MEF2. When activated, MEF2 promoted the transcription of a set of genes, including arc and synGAP, that restrict synapse number. These findings define an activity-dependent transcriptional program that may control synapse number during development.
Flavell
Steven W
SW
Neurobiology Program, Children's Hospital, and Departments of Neurology and Neurobiology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Cowan
Christopher W
CW
Kim
Tae-Kyung
TK
Greer
Paul L
PL
Lin
Yingxi
Y
Paradis
Suzanne
S
Griffith
Eric C
EC
Hu
Linda S
LS
Chen
Chinfei
C
Greenberg
Michael E
ME
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics; D003712:Dendrites / Q000502:physiology / Q000648:ultrastructure; D019706:Excitatory Postsynaptic Potentials; D020690:GTPase-Activating Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D064326:MEF2 Transcription Factors; D009154:Mutation; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D034622:RNA Interference; D051381:Rats; D020318:Rats, Long-Evans; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission; D014158:Transcription, Genetic; D014162:Transfection
D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C112202:Syngap1 protein, rat; C092069:activity regulated cytoskeletal-associated protein; D018698:Glutamic Acid; D019703:Calcineurin; D002118:Calcium