title: Opposing action of nuclear factor κB and Polo-like kinases determines a homeostatic end point for excitatory synaptic adaptation.
abstract: Homeostatic responses critically adjust synaptic strengths to maintain stability in neuronal networks. Compensatory adaptations to prolonged excitation include induction of Polo-like kinases (Plks) and degradation of spine-associated Rap GTPase-activating protein (SPAR) to reduce synaptic excitation, but mechanisms that limit overshooting and allow refinement of homeostatic adjustments remain poorly understood. We report that Plks produce canonical pathway-mediated activation of the nuclear factor κB (NF-κB) transcription factor in a process that requires the kinase activity of Plks. Chronic elevated activity, which induces Plk expression, also produces Plk-dependent activation of NF-κB. Deficiency of NF-κB, in the context of exogenous Plk2 expression or chronic elevated neuronal excitation, produces exaggerated homeostatic reductions in the size and density of dendritic spines, synaptic AMPA glutamate receptor levels, and excitatory synaptic currents. During the homeostatic response to chronic elevated activity, NF-κB activation by Plks subsequently opposes Plk-mediated SPAR degradation by transcriptionally upregulating SPAR in mouse hippocampal neurons in vitro and in vivo. Exogenous SPAR expression can rescue the overshooting of homeostatic reductions at excitatory synapses in NF-κB-deficient neurons responding to elevated activity. Our data establish an integral feedback loop involving NF-κB, Plks, and SPAR that regulates the end point of homeostatic synaptic adaptation to elevated activity and are the first to implicate a transcription factor in the regulation of homeostatic synaptic responses.
authors.affiliation: Department of Biological Chemistry and Solomon H. Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205.
authors.forename: Anca B
authors.initials: AB
authors.lastname: Mihalas
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Araki
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
authors.forename: Mollie K
authors.initials: MK
authors.lastname: Meffert
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D018091:Receptors, AMPA / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D020690:GTPase-Activating Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D018091:Receptors, AMPA; D000097869:Polo-Like Kinase 1; C543508:Sipa1l1 protein, mouse