Abstract

Spine morphogenesis mainly occurs during development as a morphological shift from filopodia-like thin protrusions to bulbous ones. We have previously reported that synaptic clustering of the actin-binding protein drebrin in dendritic filopodia governs spine morphogenesis and synaptic PSD-95 clustering. Here, we report the activity-dependent cellular mechanisms for spine morphogenesis, in which the activity of AMPA receptors (AMPARs) regulates drebrin clustering in spines by promoting drebrin stabilization. In cultured developing hippocampal neurons, pharmacological blockade of AMPARs, but not of other glutamate receptors, suppressed postsynaptic drebrin clustering without affecting presynaptic clustering of synapsin I (synapsin-1). Conversely, the enhancement of the action of AMPARs promoted drebrin clustering in spines. When we explored drebrin dynamics by photobleaching individual spines, we found that AMPAR activity increased the fraction of stable drebrin without affecting the time constant of drebrin turnover. An increase in the fraction of stable drebrin corresponded with increased drebrin clustering. AMPAR blockade also suppressed normal morphological maturation of spines and synaptic PSD-95 clustering in spines. Together, these data suggest that AMPAR-mediated stabilization of drebrin in spines is an activity-dependent cellular mechanism for spine morphogenesis.

Highlights

  • Dendritic spines are the receptive sites of most glutamatergic synapses in adult brains (Harris and Kater, 1994; Hering and Sheng, 2001)

  • We show that AMPA-receptor (AMPAR)-activity-mediated stabilization of drebrin plays a pivotal role in the drebrin clustering at postsynaptic sites that underlies spine morphogenesis during development

  • Chronic inhibition of AMPA receptors (AMPARs) causes filopodia-like thin spines during development Given the importance of AMPAR activity in drebrin clustering, which governs dendritic spine morphogenesis, we investigated whether AMPAR activity is involved in spine morphogenesis of developing hippocampal neurons in culture

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Summary

Introduction

Dendritic spines are the receptive sites of most glutamatergic synapses in adult brains (Harris and Kater, 1994; Hering and Sheng, 2001). A typical case of a synaptically functional spine is represented by a mushroom-shaped protrusion possessing a bulbous head and narrow neck (Matsuzaki et al, 2001; Noguchi et al, 2005). Spine morphogenesis during development mainly occurs as the morphological shift from filopodia, long headless protrusions, to mushroom-shaped spines (Fiala et al, 1998). Given the importance of morphological changes of spines in synaptic plasticity of mature neurons (Bourne and Harris, 2007; Segal, 2005; Yuste and Bonhoeffer, 2001), it is proposed that activity-dependent mechanisms for spine morphogenesis during development are crucial for the development and plasticity of neuronal circuits. The cellular mechanisms of the activity-dependent regulation of spine morphology during development remain unclear

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