Modulation of the Nerve Growth Factor (NGF)-TrkA signaling impacts microglial phenotype

The neurotrophin Nerve Growth Factor (NGF), known for its role in supporting neuronal survival anddifferentiation, exhibits pleiotropic effects on non-neuronal cells, particularly within the peripheralimmune system. Related to this, our work identified potent immunomodulatory properties of NGF viaTropomyosin receptor kinase A (TrkA) on cultured microglia, as NGF directs these cells toward aneuroprotective phenotype. In this study, we present in vivo evidence supporting the neuroprotectiverole of NGF signaling in murine brain microglia.First, we explored the therapeutic potential of an NGF mutein, human NGF painless (hNGFp), in aneurodevelopmental disease, Rett syndrome (RTT). Using a non-invasive intranasal delivery in femaleMeCP2+/- mice, a model for RTT, we observed a reversal of microglial morphology deficits in treatedanimals and a restoration of altered expression of key neuroimmune-communication cytokines, suchas Fractalkine, suggesting that hNGFp treatment can ameliorate symptoms in the MeCP2+/- model byexerting neuroprotection also through microglial modulation.Secondly, to directly assess the functional role of microglial NGF-TrkA signaling, we generated anovel inducible transgenic mouse [CX3CR1-CreERT/+:TrkA(fl/fl)] allowing specific TrkA deletion inmicroglia (cKO). Knocking out microglial NGF-TrkA signaling reduced microglial density andmorphological complexity, and increased phagocytosis of excitatory synaptic puncta, selectively inthe primary somatosensory cortex and hippocampus, also consequently altering memory behavior.Live imaging via two-photon microscopy revealed that branch motility in cKO microglia is increasedin baseline (augmented surveillance) and not responsive to exogenous NGF.In conclusion, our data suggest that NGF-TrkA signaling can influence pivotal microglial activities,even in pathological conditions. Modulating the NGF-TrkA axis on microglia in vivo holds promise asa broad therapeutic neuroprotective strategy.