Microglia are the brain's resident immune cells and function as the main defense against pathogens or injury. However, in the absence of disease, microglia have other functions in the normal brain. For example, previous studies showed that microglia contribute to circuit refinement and synaptic plasticity in the developing and adult brain, respectively. Thus, microglia actively participate in regulating neuronal excitability and function. Here, we report that in the cortex, but not other brain regions, a subset of microglia extend a single process that specifically associates and overlaps with the axon initial segment (AIS), the site where action potentials are generated. Similar associations were not observed with dendrites or distal axons. Microglia-AIS interactions appear early in development, persist throughout adulthood, and are conserved across species including mice, rats, and primates. However, these interactions are lost after microglial activation following brain injury, suggesting that such interactions may be part of healthy brain function. Loss of microglial CX3CR1 receptors, or the specialized extracellular matrix surrounding the AIS, did not disrupt the interaction. However, loss of AIS proteins by the neuron-specific deletion of the master AIS scaffold AnkyrinG disrupted microglia-AIS interactions. These results reveal a unique population of microglia that specifically interact with the AIS in the adult cortex.

The tet-off system has been widely used to create transgenic models of neurological disorders including Alzheimer’s, Parkinson’s, Huntington’s, and prion disease. The utility of this system lies in the assumption that the tetracycline transactivator (TTA) acts as an inert control element and does not contribute to phenotypes under study. Here we report that neuronal expression of TTA can affect hippocampal cytoarchitecture and behavior in a strain-dependent manner. While studying neurodegeneration in two tet-off Alzheimer’s disease models, we unexpectedly discovered neuronal loss within the dentate gyrus of single transgenic TTA controls. Granule neurons appeared most sensitive to TTA exposure during postnatal development, and doxycycline treatment during this period was neuroprotective. TTA-induced degeneration could be rescued by moving the transgene onto a congenic C57BL/6J background, and recurred on re-introduction of either CBA or C3H/He backgrounds. Quantitative trait analysis of B6C3 F2 TTA mice identified a region on Chromosome 14 that contains a major modifier of the neurodegenerative phenotype. Although B6 mice were resistant to degeneration, they were not ideal for cognitive testing. F1 offspring of TTA C57BL/6J and 129X1/SvJ, FVB/NJ, or DBA/1J showed improved spatial learning, but TTA expression caused subtle differences in contextual fear conditioning on two of these backgrounds indicating that strain and genotype can interact independently under different behavioral settings. All model systems have limitations that should be recognized and mitigated where possible; our findings stress the importance of mapping the effects caused by TTA alone when working with tet-off models.

Amyloid-β (Aβ) plaques are one of the central pathologies of Alzheimer’s disease (AD). Plaque formation in animal models of AD coincides with the appearance of synaptic abnormalities, aberrant neuronal excitability, and cognitive decline. Aβ plaques may disrupt neuronal excitability since they have been proposed to be synaptotoxic, to induce axonal varicosities and neurite breakage, and to significantly decrease spine density. Axon initial segments (AIS) also regulate neuronal excitability and help maintain neuronal polarity. Despite these essential functions, the effects of plaques on AIS structure have not been fully determined. Using a mouse AD model, we measured a significant decrease in the density of AIS up to 75 μm away from the center of fibrillar, thioflavin-labeled plaques. The reduction was observed in animals with both moderate and severe plaque loads, and was associated with increased densities of microglia near the plaques. Furthermore, animals with severe plaque loads had significantly reduced AIS lengths adjacent to Aβ plaques. These results suggest the local environment surrounding Aβ plaques may be harmful to the AIS. We propose that AIS loss is a previously unappreciated consequence of AD that could significantly impact brain function.

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Pyramidal neurons integrate synaptic inputs from basal and apical dendrites to generate stimulus-specific responses. It has been proposed that feed-forward inputs to basal dendrites drive a neuron’s stimulus preference, while feedback inputs to apical dendrites sharpen selectivity. However, how a neuron’s dendritic domains relate to its functional selectivity has not been demonstrated experimentally. We performed 2-photon dendritic micro-dissection on layer-2/3 pyramidal neurons in mouse primary visual cortex. We found that removing the apical dendritic tuft did not alter orientation-tuning. Furthermore, orientation-tuning curves were remarkably robust to the removal of basal dendrites: ablation of 2 basal dendrites was needed to cause a small shift in orientation preference, without significantly altering tuning width. Computational modeling corroborated our results and put limits on how orientation preferences among basal dendrites differ in order to reproduce the post-ablation data. In conclusion, neuronal orientation-tuning appears remarkably robust to loss of dendritic input.