Neuronal synapses are highly dynamic and undergo molecular and structural changes linked to the regulation of synaptic plasticity. Myosins make essential contributions to these processes by mediating actin cytoskeleton rearrangement and cargo transport.
Non-muscle myosin IIb drives actin cytoskeleton dynamics in dendritic spines in response to synaptic stimulation, promotes the maintenance of hippocampal long-term potentiation and is important for memory consolidation.
Myosin Va transports the endoplasmic reticulum into the spines of Purkinje neurons, thereby allowing cerebellar long-term depression. To achieve long-term potentiation, myosin Vb delivers AMPA receptor-carrying recycling endosomes into hippocampal spines upon synaptic stimulation.
Myosin VI associates with membranes, walks towards the actin filament's minus end and functions in AMPA receptor and type A GABA receptor trafficking. Myosin VI is required for basal synaptic transmission and brain-derived neurotrophic factor-dependent hippocampal long-term potentiation.
Synaptic myosins might be linked to psychiatric disease (non-muscle myosin IIa and myosin Vb) and neurodegenerative disease (myosin VI). Mutations in myosin Va cause severe neurological defects including ataxia and seizures. Non-muscle myosin IIb is required for normal nervous system development.
Myosins are a large family of actin-based cytoskeletal motors that use energy derived from ATP hydrolysis to generate movement and force. Myosins of classes II, V and VI have specific pre- and postsynaptic roles that are required for synapse function. They also facilitate several forms of synaptic plasticity. Interestingly, the myosins of these classes differ markedly in important aspects of their molecular mechanisms of function. Accordingly, their major roles at synapses are diverse and include the regulation of actin cytoskeleton dynamics in dendritic spines and powering of synaptic cargo transport.
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We thank J. A. Hammer III for his comments on the manuscript. The authors are supported by University Medical Center Hamburg-Eppendorf, German Research Foundation (DFG) grants KN556/4-2, KN556/6-1, GRK1459and the Hamburg excellence programme “neurodapt!” to M.K., and by a Marie Curie Career Integration Grant (PCIG11-GA-2012-321905) to W.W.
The authors declare no competing financial interests.
- Active zones
These are presynaptic specializations at which docking, priming and fusion of synaptic vesicles occur. They organize neurotransmitter release and are crucial for presynaptic plasticity.
- Dendritic spines
Small, actin-rich protrusions from a neuronal dendrite. Spines are postsynaptic compartments that receive input from presynaptic terminals.
- Long-term potentiation
(LTP). An activity-dependent, long-lasting increase in the strength of a neuronal synapse.
- Readily releasable pool
Synaptic vesicles that are docked and primed in the active zone and are immediately ready for fusion with the plasma membrane to release neurotransmitter.
- Retrograde flow
A phenomenon in which the actin subunits present within dynamic actin filaments travel away from the cell surface owing to the incorporation of new actin subunits at barbed ends located near the cell surface and owing to myosin II pulling the peripheral actin filament meshwork inwards.
- Focal adhesions
Integrin-based, complex protein assemblies that mediate cell-to-extracellular matrix contact and that are found at the termini of stress fibres.
- Myosin motor domain
A conserved, globular domain that binds actin, hydrolyses ATP and produces force. It is also known as the myosin head.
- RAB GTPases
A family of small GTPases that are anchored in diverse membranes via geranylgeranyl moieties. When bound to GTP, RAB GTPases bind effector proteins to recruit them to membranes.
- Lever arm
A rod-like element attached to the myosin motor domain that acts as a lever that amplifies the conformational changes generated in the motor domain.
- Postsynaptic density
(PSD). An electron-dense submembrane compartment in dendritic spines. It is directly opposed to the active zone and harbours neurotransmitter receptors, scaffold proteins and signalling molecules.
An inhibitor that blocks the ATPase activity of myosin II by slowing down phosphate release, thereby locking the myosin motor domain in a state of low actin affinity.
- AMPA receptor
A tetrameric glutamate receptor that mediates fast, excitatory synaptic transmission and that is composed of diverse combinations of the subunits GluA1–GluA4.
- Recycling endosomes
Membrane compartments via which endocytosed membrane receptors are recycled back to the plasma membrane.
- Long-term depression
(LTD). A long-lasting reduction in the strength of a neuronal synapse following certain stimuli.
- Endoplasmic reticulum
A cellular organelle that forms an interconnected network of tubules and cisternae and that is crucial for protein secretion, membrane protein translation and lipid synthesis. Furthermore, it serves as an intracellular Ca2+ store involved in regulating cytosolic Ca2+ concentration.
A state of severe hyperextension and spasticity caused by spasm of the axial muscles along the spinal column.
A proliferation of astrocytes that can be a consequence of neurodegenerative processes or epilepsy.
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Kneussel, M., Wagner, W. Myosin motors at neuronal synapses: drivers of membrane transport and actin dynamics. Nat Rev Neurosci 14, 233–247 (2013). https://doi.org/10.1038/nrn3445
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