Structural plasticity and homeostasis enable the brain to adapt to environmental changes and learning. However, the underlying molecular mechanisms are poorly understood. In humans, these processes depend on neurotrophins functioning through Trk and p75NTR receptors. Drosophila neurotrophins bind Toll receptors instead. Thus, understanding how Tolls operate is important to understand the brain. Here, I investigated the function of Toll-2 in the Drosophila brain. Using CRISPR/Cas9, I generated mutant and knock-in Toll-2 alleles and showed that Toll-2 is expressed in neurons, and loss of Toll-2 function impaired behaviour, longevity, connectivity and cell survival during development. In the central brain, Toll-2 knock-down reduced cell number, whereas Toll-2 over-expression increased cell number. Interference with Toll-2 function, neuronal activity or downstream signalling effectors at the adult critical period only, also altered cell number in the central brain and medulla. However, these manipulations did not affect Kenyon cell number. Multiple Tolls are expressed in the brain, and together they regulate brain size and shape. Loss of multiple Tolls affected Kenyon cell clusters, meaning that Tolls redundantly provide robustness to mushroom body cells. To conclude, Tolls regulate brain development, and structural plasticity in the adult brain involves changes in neuronal number regulated via cell signalling.