Toll and kinase-less Trk receptors in concert drive a novel mechanism of structural synaptic plasticity.

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The nervous system changes throughout life, as neurons, neurites and synapses are generated and eliminated. Structural brain plasticity enables us to learn and adapt to change, and destructive change maintains structural homeostasis and integrity, enabling further adaptation. Such neuronal remodelling could be structural correlates of brain function. Thus, unravelling the relationship between structural plasticity/homeostasis and neuronal activity is a gateway to understanding how the brain works. The balance between structural plasticity and homeostasis is also essential for brain health, and its breakdown leads to brain tumours, neurodegeneration, motor and psychiatric disorders. Conversely, increasing brain plasticity is a key strategy to tackle brain disease. Brain disease constitutes the greatest disease burden in Europe, costing over double of cancer and cardiac diseases put together. Most brain diseases - from anxiety and depression, to epilepsy, autism, neurodegeneration, e.g. Alzheimer's and Parkinson's diseases, and neuroinflammation - involve problems with the neurotrophins (NTs) and/or Toll-Like-Receptors (TLRs). NTs are key plasticity factors, and promote neuronal survival, connectivity, synaptic formation, learning and long-term memory, through Trk receptors and tyrosine kinase signaling downstream. However, paradoxically, the most abundant Trk isoforms in the human adult brain lack the tyrosine kinase, but their neuronal functions are unknown. TLRs are best known for underlying innate immunity. TLRs are also found in all neurons, however their neuronal functions are largely unknown, and their ligands in the brain are also unknown. Altogether, the molecular mechanisms regulating nervous system structural plasticity and homeostasis are little understood. Discovering novel mechanisms to enhance brain plasticity is an urgent neuroscience goal.We recently discovered a previously unforeseen relationship between NTs, kinase-less Trk and Toll receptors in the central nervous system (CNS) of the fruit-fly, Drosophila. There are no full-length Trks in Drosophila, and instead, Trk homologues encoded by the kekkon (kek) genes lack the tyrosine kinase. Thus, Drosophila offers a golden opportunity to investigate the functions of truncated Trk receptors in vivo. The fruit-fly is the most powerful model organism for functional genetic analysis in vivo, offering from neural circuit to synaptic resolution and behaviour.We discovered that Drosophila neurotrophins (DNTs) bind Toll receptors to regulate neuronal number, connectivity and behaviour, and bind Keks to promote structural synaptic plasticity, e.g. synaptic bouton formation and axonal arbor complexity. We suspect they also function together. We hypothesize that a feedback loop between pre- and post-synaptic cells, involving post-synaptic translation of DNT2 and a Kek-Toll receptor complex, modulates synaptic function and promotes structural changes in neurons in response to neuronal activity. We will test this hypothesis at the glutamatergic neuromuscular junction (NMJ) of the Drosophila larva by: (1) Determining the mechanism of Kek-6 action, validating candidates we have identified. (2) Working out how Keks and Tolls interact, and resolving the Kek-Toll code. As there are multiple Keks and Tolls, distinct pairs could be characteristic of neuronal type, or of distinct responses to neuronal activity by dendrites and axons. (3) We will select 2-3 Kek-Toll pairs with their downstream factors, to test whether and how they modulate synaptic function and structural changes in neurons in response to neuronal activity.The outcome will be the identification of a novel, unanticipated molecular mechanism for nervous system structural plasticity. Even if not all details were to be evolutionarily conserved in humans, our framework will provide compelling and incisive predictions to test in rodents, for the benefit of understanding the human CNS, in health and disease.