Neurotransmitter

Cell biology

Synaptic plasticity

Neuroscience

Biology

Plexin

Metaplasticity

Vesicle

Receptor

Postsynaptic potential

Neurotransmission

Synaptic scaling

Neurotransmitter receptor

Axon

Axon guidance

Genetics

Homeostasis

Membrane

Semaphorin

Homeostatic plasticity

Central nervous system

Synaptic vesicle

Nonsynaptic plasticity

Nervous system

Nature

At the neuromuscular junction in Drosophila, signalling from postsynaptic Sema2b to presynaptic PlexB controls presynaptic homeostatic plasticity through Mical-mediated regulation of the readily releasable pool of synaptic vesicles. Some key regulators of embryonic neuronal development, such as the semaphorin proteins and their plexin receptors, are also expressed in the adult brain, but their function there is not clear. Working at the neuromuscular junction in Drosophila, Graeme Davis and colleagues now report that postsynaptic, secreted Sema2b acts as a retrograde signal on presynaptic PlexB receptors to modify the actin cytoskeleton and control the fraction of synaptic vesicles available for neurotransmitter release. Involving semaphorins and plexins in the stabilization of adult synaptic physiology provides a new, molecular handle for investigating the potential role of maladaptive homeostatic plasticity in neurological and psychiatric diseases. Homeostatic signalling systems ensure stable but flexible neural activity and animal behaviour1,2,3,4. Presynaptic homeostatic plasticity is a conserved form of neuronal homeostatic signalling that is observed in organisms ranging from Drosophila to human1,5. Defining the underlying molecular mechanisms of neuronal homeostatic signalling will be essential in order to establish clear connections to the causes and progression of neurological disease. During neural development, semaphorin–plexin signalling instructs axon guidance and neuronal morphogenesis6,7,8,9,10. However, semaphorins and plexins are also expressed in the adult brain11,12,13,14,15,16. Here we show that semaphorin 2b (Sema2b) is a target-derived signal that acts upon presynaptic plexin B (PlexB) receptors to mediate the retrograde, homeostatic control of presynaptic neurotransmitter release at the neuromuscular junction in Drosophila. Further, we show that Sema2b–PlexB signalling regulates presynaptic homeostatic plasticity through the cytoplasmic protein Mical and the oxoreductase-dependent control of presynaptic actin. We propose that semaphorin–plexin signalling is an essential platform for the stabilization of synaptic transmission throughout the developing and mature nervous system. These findings may be relevant to the aetiology and treatment of diverse neurological and psychiatric diseases that are characterized by altered or inappropriate neural function and behaviour.

Retrograde semaphorin–plexin signalling drives homeostatic synaptic plasticity