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.

Therapeutic inhibition of soluble brain TNF promotes remyelination by increasing myelin phagocytosis by microglia

“…DNase-treated RNA samples were subjected to quantitative PCR (qPCR) using a QuantiFast SYBR Green RT-PCR kit (Qiagen; catalog 204154), per manufacturer's instructions. All reactions were performed using a LightCycler (Roche Diagnostics) as described (64). Values were normalized using the respective values for Gusb, or Gapdh (for Arg1, Chil3, Il1β, and Nos2).…”

(Putative) sex differences in neuroimmune modulation of memory

“…Microglia-specific intracellular signaling and gene expression are also important for memory tasks. For example, IKKb in microglia, but not neurons, is required for instrumental conditioning (Kyrargyri et al, 2014). Similarly, microglia-specific BDNF signaling is required for spine development and both motor learning and tone-dependent fear conditioning (Parkhurst et al, 2013).…”

“…Female Male and female Sex not specified Ostroff et al, 2014Maggi et al, 2011Acaz-Fonseca et al, 2015Habbas et al, 2015Milior et al, 2016Almoda et al, 2015* Pascual et al, 2012Rogers et al, 2011Vasek et al, 2016* Nimmerjahn et al, 2005Kyrargyri et al, 2014Schwarz et al, 2012Parkhurst et al, 2013Delpech et al, 2015Sorge et al, 2011Tanaka et al, 2006Sorge et al, 2015Zhong et al, 2010Riazi et al, 2015 Neuroimmune modulation of adult neurogenesis…”

Transcriptional Control of Synaptic Plasticity by Transcription Factor NF-κB

“…Despite the fact that astrocyte-specific target genes of NF- κ B have not been investigated in this study, the data strongly suggest that astrocytes positively modulate the expression of synaptic proteins by neurons. To investigate the contribution of microglial NF- κ B to learning and memory formation in mice, IKK2 has been deleted in myeloid cells including microglia ( mIKK2KO ) recently [ 24 ]. Among various well-known target genes of NF- κ B only transcript levels for Interleukin-1β were altered in the brains of mIKK2KO mice, which coincided with transiently increased short-term fear memory of the transgenic mice.…”

“…Among various well-known target genes of NF- κ B only transcript levels for Interleukin-1β were altered in the brains of mIKK2KO mice, which coincided with transiently increased short-term fear memory of the transgenic mice. This observation reveals a novel and unexpected role for microglial IKK2/NF- κ B in the homeostatic regulation of synaptic plasticity [ 24 ]. Taken together, synaptic plasticity requires the adaptive regulation of κ B-responsive genes not only within the pre- and postsynaptic neuron, but also within adjacent astro- and microglial cells.…”