A Toll-receptor map underlies structural brain plasticity.

Experience alters brain structure, but the underlying mechanism remained unknown. Structural plasticity reveals that brain function is encoded in generative changes to cells that compete with destructive processes driving neurodegeneration. At an adult critical period, experience increases fiber number and brain size in Drosophila. Here, we asked if Toll receptors are involved. Tolls demarcate a map of brain anatomical domains. Focusing on Toll-2, loss of function caused apoptosis, neurite atrophy and impaired behaviour. Toll-2 gain of function and neuronal activity at the critical period increased cell number. Toll-2 induced cycling of adult progenitor cells via a novel pathway, that antagonized MyD88-dependent quiescence, and engaged Weckle and Yorkie downstream. Constant knock-down of multiple Tolls synergistically reduced brain size. Conditional over-expression of Toll-2 and wek at the adult critical period increased brain size. Through their topographic distribution, Toll receptors regulate neuronal number and brain size, modulating structural plasticity in the adult brain.

Everything that you experience leaves its mark on your brain. When you learn something new, the neurons involved in the learning episode grow new projections and form new connections. Your brain may even produce new neurons. Physical exercise can induce similar changes, as can taking antidepressants. By contrast, stress, depression, ageing and disease can have the opposite effect, triggering neurons to break down and even die. The ability of the brain to change in response to experience is known as structural plasticity, and it is in a tug-of-war with processes that drive neurodegeneration. Structural plasticity occurs in other species too: for example, it was described in the fruit fly more than a quarter of a century ago. Yet, the molecular mechanisms underlying structural plasticity remain unclear. Li et al. now show that, in fruit flies, this plasticity involves Toll receptors, a family of proteins present in the brain but best known for their role in the immune system. Fruit flies have nine different Toll receptors, the most abundant being Toll-2. When activated, these proteins can trigger a series of molecular events in a cell. Li et al. show that increasing the amount of Toll-2 in the fly brain makes the brain produce new neurons. Activating neurons in a brain region has the same effect, and this increase in neuron number also depends on Toll-2. By contrast, reducing the amount of Toll-2 causes neurons to lose their projections and connections, and to die, and impairs fly behaviour. Li et al. also show that each Toll receptor has a unique distribution across the fly brain. Different types of experiences activate different brain regions, and therefore different Toll receptors. These go on to trigger a common molecular cascade, but they modulate it such as to result in distinct outcomes. By working together in different combinations, Toll receptors can promote either the death or survival of neurons, and they can also drive specific brain cells to remain dormant or to produce new neurons. By revealing how experience changes the brain, Li et al. provide clues to the way neurons work and form; these findings may also help to find new treatments for disorders that change brain structure, such as certain psychiatric conditions. Toll-like receptors in humans could thus represent a promising new target for drug discovery.

The neuronal ceroid lipofuscinosis protein Cln7 functions in the postsynaptic cell to regulate synapse development.

The neuronal ceroid lipofuscinoses (NCLs) are a group of fatal, monogenic neurodegenerative disorders with an early onset in infancy or childhood. Despite identification of the genes disrupted in each form of the disease, their normal cellular role and how their deficits lead to disease pathology is not fully understood. Cln7, a major facilitator superfamily domain-containing protein, is affected in a late infantile-onset form of NCL. Cln7 is conserved across species suggesting a common function. Here we demonstrate that Cln7 is required for the normal growth of synapses at the Drosophila larval neuromuscular junction. In a Cln7 mutant, synapses fail to develop fully leading to reduced function and behavioral changes with dysregulation of TOR activity. Cln7 expression is restricted to the post-synaptic cell and the protein localizes to vesicles immediately adjacent to the post-synaptic membrane. Our data suggest an involvement for Cln7 in regulating trans-synaptic communication necessary for normal synapse development.