Abstract
BackgroundMicroglia play a key role in neuronal circuit and synaptic maturation in the developing brain. In the healthy adult, however, their role is less clear: microglial hyperactivation in adults can be detrimental to memory due to excessive synaptic pruning, yet learning and memory can also be impaired in the absence of these cells. In this study, we therefore aimed to determine how microglia contribute to short-term memory in healthy adults.MethodsTo this end, we developed a Cx3cr1-Dtr transgenic Wistar rat with a diphtheria toxin receptor (Dtr) gene inserted into the fractalkine receptor (Cx3cr1) promoter, expressed on microglia and monocytes. This model allows acute microglial and monocyte ablation upon application of diphtheria toxin, enabling us to directly assess microglia’s role in memory.ResultsHere, we show that short-term memory in the novel object and place recognition tasks is entirely unaffected by acute microglial ablation. However, when microglia repopulate the brain after depletion, learning and memory performance in these tasks is improved. This transitory memory enhancement is associated with an ameboid morphology in the newly repopulated microglial cells and increased astrocyte density that are linked with a higher density of mature hippocampal synaptic spines and differences in pre- and post-synaptic markers.ConclusionsThese data indicate that glia play a complex role in the healthy adult animal in supporting appropriate learning and memory and that subtle changes to the function of these cells may strategically enhance memory.
Highlights
Microglia play a key role in neuronal circuit and synaptic maturation in the developing brain
The Cx3cr1-diphtheria toxin receptor (Dtr) rat allows selective inducible, reversible ablation of microglia As we have previously reported for other behaviors and brain regions [22], hippocampal microglial numbers and hippocampal Cx3cr1 mRNA expression were not affected under basal conditions, i.e., by the presence of the Dtr alone (Additional file 2: Figure S1)
For the Y maze, at 48 h after diphtheria toxin (DT), the Cx3cr1-Dtr rats showed an increased latency to enter the novel arm compared with the wt controls (Fig. 3a)
Summary
Microglia play a key role in neuronal circuit and synaptic maturation in the developing brain. Their role is less clear: microglial hyperactivation in adults can be detrimental to memory due to excessive synaptic pruning, yet learning and memory can be impaired in the absence of these cells. Microglial cells are a major immune cell population in the brain that coordinate synaptic pruning during development and central responses to pathogens and brain injury in the mature animal [9,10,11,12,13]. It is clear that appropriate synaptic pruning and clearance of excess neurons by microglia during early development is important for the maturation of neural circuits, for instance, with microglial knockout mice displaying immature excitatory synapse functioning [14,15,16]. The role of microglia in learning and memory in the mature animal is less clear
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