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The Journal of Neuroscience, July 16, 2003, 23(15):6327-6337
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Inhibition of Dendritic Spine Morphogenesis and Synaptic Transmission by Activity-Inducible Protein Homer1a
Carlo Sala,1 Kensuke Futai,2,4 Kenji Yamamoto,2 Paul F. Worley,5 Yasunori Hayashi,2 andMorgan Sheng2,3 1Consiglio Nazionale delle Ricerche Institute of Neuroscience, Cellular and Molecular Pharmacology, Department of Pharmacology, University of Milan, 20129 Milan, Italy, 2RIKEN—Massachusetts Institute of Technology Neuroscience Research Center, The Picower Center for Learning and Memory, Department of Brain and Cognitive Science, and 3Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, 4Laboratory for Neural Architecture, Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan, and 5Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
The postsynaptic density (PSD) proteins Shank and Homer cooperate to induce the maturation and enlargement of dendritic spines (Sala et al., 2001). Homer1a is an activity-inducible short-splice variant of Homer that lacks dimerization capacity. Here, we show that Homer1a reduces the density and size of dendritic spines in cultured hippocampal neurons in correlation with an inhibition of Shank targeting to synapses. Expression of Homer1a also decreases the size of PSD-95 clusters, the number of NMDA receptor clusters, and the level of surface AMPA receptors, implying a negative effect on the growth of synapses. In parallel with the morphological effects on synapses, Homer1a-expressing neurons show diminished AMPA and NMDA receptor postsynaptic currents. All of these outcomes required the integrity of the Ena/VASP Homology 1 domain of Homer1a that mediates binding to the PPXXF motif in Shank and other binding partners. Overexpression of the C-terminal region of Shank containing the Homer binding site causes effects similar to those of Homer1a. These data indicate that an association between Shank and the constitutively expressed long-splice variants of Homer (e.g., Homer1b/c) is important for maintaining dendritic-spine structure and synaptic function. Because Homer1a expression is induced by synaptic activity, our results suggest that this splice variant of Homer operates in a negative feedback loop to regulate the structure and function of synapses in an activity-dependent manner.
Key words: dendritic spine; Shank; AMPA receptor; NMDA receptor; postsynaptic density; synaptic plasticity
Received Feb. 12, 2003; revised May. 6, 2003; accepted May. 7, 2003.
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