BDNF/PROBDNF SIGNALING REGULATES MICROGLIAL PHENOTYPE AND INFLAMMATORY RESPONSES IN THE MOUSE HIPPOCAMPUS

Brain-derived neurotrophic factor (BDNF) and its precursor proBDNF regulate neuronal development, plasticity, and learning and memory processes by binding to their receptors tropomyosin-related kinase receptor type B (TrkB) and p75 neurotrophin receptor (p75^NTR). In a yin–yang relationship, BDNF–TrkB promotes neuronal survival and synaptic strengthening, while proBDNF–p75^NTR drives apoptosis and synaptic weakening. Moreover, microglia have been shown to be responsive to BDNF. In the brain, BDNF levels decrease, while those of proBDNF increase with aging, a condition associated with cognitive decline and pro-inflammatory activation of microglia. However, whether an altered balance in BDNF/proBDNF signaling contributes to age-related microglial changes remains unclear. To address this question, pro-inflammatory activation of microglia was induced by lipopolysaccharide (LPS) in primary pure microglia, astrocyte, and mixed glial cultures previously treated with BDNF/proBDNF. Pure cultures were used to assess cell type-specific responses, while mixed glial cultures allowed assessment of the role of microglia-astrocyte interactions. Low concentrations of BDNF and proBDNF attenuate LPS-induced pro-inflammatory cytokine production in a dose-, sex-, and astrocyte-dependent manner. Microglial morphology reflects their activation state and functional phenotype. To address the signaling pathway involved in the anti-inflammatory effect of BDNF/proBDNF, time-lapse two-photon imaging was used in acute hippocampal slices to monitor microglial structural changes over time following BDNF scavenging or p75^NTR loss of function. Both conditions significantly affect microglial structure and dynamics, indicating that BDNF/proBDNF signaling may influence microglial activation states, potentially contributing to the neuroinflammatory processes occurring during aging.