title: Differential contributions of microglial and neuronal IKKβ to synaptic plasticity and associative learning in alert behaving mice.
abstract: Microglia are CNS resident immune cells and a rich source of neuroactive mediators, but their contribution to physiological brain processes such as synaptic plasticity, learning, and memory is not fully understood. In this study, we used mice with partial depletion of IκB kinase β, the main activating kinase in the inducible NF-κB pathway, selectively in myeloid lineage cells (mIKKβKO) or excitatory neurons (nIKKβKO) to measure synaptic strength at hippocampal Schaffer collaterals during long-term potentiation (LTP) and instrumental conditioning in alert behaving individuals. Resting microglial cells in mIKKβKO mice showed less Iba1-immunoreactivity, and brain IL-1β mRNA levels were selectively reduced compared with controls. Measurement of field excitatory postsynaptic potentials (fEPSPs) evoked by stimulation of the CA3-CA1 synapse in mIKKβKO mice showed higher facilitation in response to paired pulses and enhanced LTP following high frequency stimulation. In contrast, nIKKβKO mice showed normal basic synaptic transmission and LTP induction but impairments in late LTP. To understand the consequences of such impairments in synaptic plasticity for learning and memory, we measured CA1 fEPSPs in behaving mice during instrumental conditioning. IKKβ was not necessary in either microglia or neurons for mice to learn lever-pressing (appetitive behavior) to obtain food (consummatory behavior) but was required in both for modification of their hippocampus-dependent appetitive, not consummatory behavior. Our results show that microglia, through IKKβ and therefore NF-κB activity, regulate hippocampal synaptic plasticity and that both microglia and neurons, through IKKβ, are necessary for animals to modify hippocampus-driven behavior during associative learning.
authors.affiliation: Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, 11521, Greece.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Kyrargyri
authors.forename: Germán
authors.initials: G
authors.lastname: Vega-Flores
authors.forename: Agnès
authors.initials: A
authors.lastname: Gruart
authors.forename: José M
authors.initials: JM
authors.lastname: Delgado-García
authors.forename: Lesley
authors.initials: L
authors.lastname: Probert
mesh_terms: D000818:Animals; D001066:Appetite / Q000235:genetics; D001522:Behavior, Animal; D003214:Conditioning, Classical; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005247:Feeding Behavior / Q000502:physiology; D006624:Hippocampus / Q000502:physiology*; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics*; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism* / Q000502:physiology; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000378:metabolism* / Q000502:physiology
chemical_list: D051550:I-kappa B Kinase
keywords: NF-κB activity; behavior; conditional knockout mice; microglia; synaptic plasticity