Abstract
Dendritic spines in hippocampal neurons mature from a filopodia-like precursor into a mushroom-shape with an enlarged post-synaptic density (PSD) and serve as the primary post-synaptic location of the excitatory neurotransmission that underlies learning and memory. Using myosin II regulatory mutants, inhibitors, and knockdowns, we show that non-muscle myosin IIB (MIIB) activity determines where spines form and whether they persist as filopodia-like spine precursors or mature into a mushroom-shape. MIIB also determines PSD size, morphology, and placement in the spine. Local inactivation of MIIB leads to the formation of filopodia-like spine protrusions from the dendritic shaft. However, di-phosphorylation of the regulatory light chain on residues Thr18 and Ser19 by Rho kinase is required for spine maturation. Inhibition of MIIB activity or a mono-phosphomimetic mutant of RLC similarly prevented maturation even in the presence of NMDA receptor activation. Expression of an actin cross-linking, non-contractile mutant, MIIB R709C, showed that maturation into a mushroom-shape requires contractile activity. Loss of MIIB also leads to an elongated PSD morphology that is no longer restricted to the spine tip; whereas increased MIIB activity, specifically through RLC-T18, S19 di-phosphorylation, increases PSD area. These observations support a model whereby myosin II inactivation forms filopodia-like protrusions that only mature once NMDA receptor activation increases RLC di-phosphorylation to stimulate MIIB contractility, resulting in mushroom-shaped spines with an enlarged PSD.
Highlights
Dendritic spines are the primary post-synaptic sites of excitatory neurotransmission in the brain [1]
Myosin IIB Regulates Spine Morphology and Dynamics MIIB localizes to dendritic protrusions of various morphologies, including filopodia-like protrusions, as well as thin, stubby and mushroom-shaped spines (Fig. 1A)
Of the MII isoforms, MIIB is the predominant one found in hippocampal neurons, and its activity and effective affinity for actomyosin filaments is regulated by regulatory light chain (RLC) [13,14]
Summary
Dendritic spines are the primary post-synaptic sites of excitatory neurotransmission in the brain [1] They are highly dynamic structures that develop from exploratory, filopodia-like processes into a compact, mushroom-shaped structure with a highly organized post-synaptic density (PSD) located at the tip [2,3]. Appropriate spine density, morphology, and PSD organization are critical for the neuronal function that underlies learning and memory [7,8]. Myosin IIB (MIIB), the predominant non-muscle myosin II isoform found in brain, contributes to actin organization in most cell types through its cross-linking and contractile properties and is implicated in spine morphology [13,14,15]. More recent evidence points to MIIB as a potentially important regulator of the spine dynamics underlying learning and memory [15,18,19]. While the importance of MIIB seems clear, the mechanism by which it shapes spine morphology is unknown
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