Synaptic connections between hippocampal mossy fibers (MFs) and CA3 pyramidal neurons are essential for contextual memory encoding, but the molecular mechanisms regulating MF-CA3 synapses during memory formation and the exact nature of this regulation are poorly understood. Here we report that the activity-dependent transcription factor Npas4 selectively regulates the structure and strength of MF-CA3 synapses by restricting the number of their functional synaptic contacts without affecting the other synaptic inputs onto CA3 pyramidal neurons. Using an activity-dependent reporter, we identified CA3 pyramidal cells that were activated by contextual learning and found that MF inputs on these cells were selectively strengthened. Deletion of Npas4 prevented both contextual memory formation and this learning-induced synaptic modification. We further show that Npas4 regulates MF-CA3 synapses by controlling the expression of the polo-like kinase Plk2. Thus, Npas4 is a critical regulator of experience-dependent, structural, and functional plasticity at MF-CA3 synapses during contextual memory formation. Weng et al. report that the transcription factor Npas4 selectively regulates the number of functional synaptic contacts between CA3 pyramidal neurons and mossy fibers, allowing for learning-induced modification of MF-CA3 synapses during contextual memory formation.
Bibliographical noteFunding Information:
We thank C. Mark Fletcher and Charles Jennings for critical reading of the manuscript; Matthew Wilson, Howard Eichenbaum, and members of the Lin lab for discussions and comments regarding the study; Qiang Chang for kindly providing the BDNF flx/flx mice; Mollie Meffert for kindly providing the Plk2 and dnPlk2 constructs; and Rachel Schecter for help with the stick and stain technique. We are grateful to Li-Huei Tsai and the Picower Institute for Learning and Memory for sharing their microscopy resources. This work was funded by a Swedish Brain Foundation research fellowship (to A.T.S.), Swiss National Science Foundation SNF171978 (to K.Z.), Burroughs Wellcome Fund Career Awards at the Scientific Interface, the Searle Scholars Program , Packard award in Science and Engineering, NARSAD Young Investigator Award, the JBP Foundation , NCSOFT Cultural Foundation, and NIH grant NS090473 (to K.C.), the JPB Foundation (to W.X.), NIH grants DA017392 and MH081935 (to P.E.C.), and the James H. Ferry Fund and NIH grants MH091220 , NS088421 , and DC014701 (to Y.L.).
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