Inhibition of Dendritic Spine Morphogenesis and Synaptic Transmission by Activity-Inducible Protein Homer1a

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.