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Regulation of synapse structure and function by distinct myosin II motors.

ABSTRACT: Ongoing synaptic function and rapid, bidirectional plasticity are both controlled by regulatory mechanisms within dendritic spines. Spine actin dynamics maintain synapse structure and function, and cytoskeletal rearrangements in these structures trigger structural and functional plasticity. Therefore, proteins that interact with actin filaments are attractive candidates to regulate synaptic actin dynamics and, thus, synapse structure and function. Here, we have cloned the rat isoform of class II myosin heavy chain MyH7B in brain. Unexpectedly, this isoform resembles muscle-type myosin II rather than the ubiquitously expressed nonmuscle myosin II isoforms, suggesting that a rich functional diversity of myosin II motors may exist in neurons. Indeed, reducing the expression of MyH7B in mature neurons caused profound alterations to dendritic spine structure and excitatory synaptic strength. Structurally, dendritic spines had large, irregularly shaped heads that contained many filopodia-like protrusions. Neurons with reduced MyH7B expression also had impaired miniature EPSC amplitudes accompanied by a decrease in synaptic AMPA receptors, which was linked to alterations of the actin cytoskeleton. MyH7B-mediated control over spine morphology and synaptic strength was distinct from that of a nonmuscle myosin, myosin IIb. Interestingly, when myosin IIb expression and MyH7B expression were simultaneously knocked-down in neurons, a third, more pronounced phenotype emerged. Together, our data provide evidence that distinct myosin II isoforms work together to regulate synapse structure and function in cultured hippocampal neurons. Thus, myosin II motor activity is emerging as a broad regulatory mechanism for control over complex actin networks within dendritic spines.

SUBMITTER: Rubio MD

PROVIDER: S-EPMC3074980 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Electrical synapses are neuronal gap junction (GJ) channels associated with a macromolecular complex called the electrical synapse density (ESD), which regulates development and dynamically modifies electrical transmission. However, the proteomic makeup and molecular mechanisms utilized by the ESD that direct electrical synapse formation are not well understood. Using the Mauthner cell of zebrafish as a model, we previously found that the intracellular scaffolding protein ZO1b is a member of the ESD, localizing postsynaptically, where it is required for GJ channel localization, electrical communication, neural network function, and behavior. Here, we show that the complexity of the ESD is further diversified by the genomic structure of the ZO1b gene locus. The ZO1b gene is alternatively initiated at three transcriptional start sites resulting in isoforms with unique N-termini that we call ZO1b-Alpha, -Beta, and -Gamma. We demonstrate that ZO1b-Beta and ZO1b-Gamma are broadly expressed throughout the nervous system and localize to electrical synapses. By contrast, ZO1b-Alpha is expressed mainly non-neuronally and is not found at synapses. We generate mutants in all individual isoforms, as well as double mutant combinations in cis on individual chromosomes, and find that ZO1b-Beta is necessary and sufficient for robust GJ channel localization. ZO1b-Gamma, despite its localization to the synapse, plays an auxiliary role in channel localization. This study expands the notion of molecular complexity at the ESD, revealing that an individual genomic locus can contribute distinct isoforms to the macromolecular complex at electrical synapses. Further, independent scaffold isoforms have differential contributions to developmental assembly of the interneuronal GJ channels. We propose that ESD molecular complexity arises both from the diversity of unique genes and from distinct isoforms encoded by single genes. Overall, ESD proteomic diversity is expected to have critical impacts on the development, structure, function, and plasticity of electrical transmission.

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Regulation of synapse structure and function by distinct myosin II motors.

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