Differential contributions of microglial and neuronal IKKβ to synaptic plasticity and associative learning in alert behaving mice.

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 IjB kinase b, the main activating kinase in the inducible NF-jB pathway, selectively in myeloid lineage cells (mIKKbKO) or excitatory neurons (nIKKbKO) to measure synaptic strength at hippocampal Schaffer collaterals during longterm potentiation (LTP) and instrumental conditioning in alert behaving individuals. Resting microglial cells in mIKKbKO mice showed less Iba1-immunoreactivity, and brain IL-1b mRNA levels were selectively reduced compared with controls. Measurement of field excitatory postsynaptic potentials (fEPSPs) evoked by stimulation of the CA3-CA1 synapse in mIKKbKO mice showed higher facilitation in response to paired pulses and enhanced LTP following high frequency stimulation. In contrast, nIKKbKO 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. IKKb 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 hippocampusdependent appetitive, not consummatory behavior. Our results show that microglia, through IKKb and therefore NF-jB activity, regulate hippocampal synaptic plasticity and that both microglia and neurons, through IKKb, are necessary for animals to modify hippocampus-driven behavior during associative learning.