At least in my hands, I got a massive microglial proliferation after depletion using the DTR model. In less than 48 hours after DT administration more than 90% of Iba1+ cells are BrdU+. The only way I found to sustain the depletion was using CSF1R antagonists at the same time. 

Both approaches have caveats. CX3CR1 is also expressed in lymphocytes, NK cells and peritoneal macrophages between other cell types. CSF1R antagonist could definitely influence peripheral macrophages activity but it seems not required for survival as it happens with microglia. Blood monocytes and tissue resident macrophages number are unchanged when mice are treated with PLX compounds.

You can not knock out microglia. however, there exists CD11b-Tk mouse in which you can deplete part of actively replicating microglia by treating animals with gancyclovir drug. If you are asking for a mouse where you can delete a gene specifically in microglia then you can lookup for CX3CR1 ERT2-Cre mouse from steffan Jung lab.

An alternate method would be to deplete microglia.

There is a paper published by Kim Green's group from the University of California, Irvine, that found a specific way to target only microglia utilizing a CSF1R inhibitor.

You can check out his work on research gate as well...

Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain.. Available from: https://www.researchgate.net/publication/261756234_Colony-stimulating_factor_1_receptor_signaling_is_necessary_for_microglia_viability_unmasking_a_microglia_progenitor_cell_in_the_adult_brain [accessed Mar 21, 2015].

Article Colony-Stimulating Factor 1 Receptor Signaling Is Necessary ...

Do you really want to get rid of them or rather target microglia by Cre-loxP?

yes, I would prefer to get rid of them.

You could use Dan Littman's cx3cr1 cre-ERT mice (http://jaxmice.jax.org/strain/021160.html) with Ari Waisman's Rosa26 DTA conditional strain (http://jaxmice.jax.org/strain/007900.html). that would allow you to get rid of them in adult mice by injecting tamoxifen, thereby circumventing any embryonic lethality. On top of it the cre strain has a yfp, so you can check whether other cells are affected to make sure this works for you. There will be another cx3cr1 cre strain without yfp and ert inducibility, but (unlike the directly targeted mouse from Littman's lab) it is a bac transgene mouse, so no one knows where it integrates and you can't track the targeted cells that easily.

Hope I could help :)

I don´t recommend you to use Cre-LoxP technology to deplete microglia because assuming 100% of recombination (which never happens) the depletion is gonna be only transient and you would need to keep injecting tamoxifen daily. Maybe you can deal with that if you want to determine the role of microglia in a short period of time but not feasible for a chronic disease model since tamoxifen is really toxic.

So far, as Chandra mentioned the best model to get rid of microglia is targeting CSF1R pharmacologically. Even though with this model you need to administrate the drug constantly because otherwise microglial cells come back really fast within 1-3 days after drug removal. 

I just checked the paper and with the PLX3397 treatment they claim a >90% depletion after 7 days of treatment, as compared to 99.1% with the DTR model within one day of DTA (two doses of tamoxifen 30 days prior to activate Cre and one injection of DTA).

The beauty of the loxP system in this case is that you only need recombination of one allele to express DTR (Parkhurst paper). They also showed limited repopulation within the following 7 days, while the Green paper saw quick repopulation (on day 7 the repopulating cells were already exceeding control numbers).

Furthermore, the question stated that other macrophages should be affected as little as possible. While targeting with CX3CR1 does target some macrophage and DC subpopulation (in the gut), the CSFR inhibitor most certainly affects most macrophages, in particular if you have to give it continuously.

I suppose it depends on the experimental goal what the best solution is but looking at the data I disagree that it is a less efficient approach.

At least in my hands, I got a massive microglial proliferation after depletion using the DTR model. In less than 48 hours after DT administration more than 90% of Iba1+ cells are BrdU+. The only way I found to sustain the depletion was using CSF1R antagonists at the same time. 

Both approaches have caveats. CX3CR1 is also expressed in lymphocytes, NK cells and peritoneal macrophages between other cell types. CSF1R antagonist could definitely influence peripheral macrophages activity but it seems not required for survival as it happens with microglia. Blood monocytes and tissue resident macrophages number are unchanged when mice are treated with PLX compounds.