Huntingtin coordinates dendritic spine morphology and function through cofilin-mediated control of the actin cytoskeleton.

Compelling evidence indicates that in Huntington's disease (HD), mutation of huntingtin (HTT) alters several aspects of early brain development such as synaptogenesis. It is not clear to what extent the partial loss of wild-type HTT function contributes to these abnormalities. Here we investigate the function of HTT in the formation of spines. Although larger spines normally correlate with more synaptic activity, cell-autonomous depletion of HTT leads to enlarged spines but reduced excitatory synaptic function. We find that HTT is required for the proper turnover of endogenous actin and to recruit AMPA receptors at active synapses; loss of HTT leads to LIM kinase (LIMK) hyperactivation, which maintains cofilin in its inactive state. HTT therefore influences actin dynamics through the LIMK-cofilin pathway. Loss of HTT uncouples spine structure from synaptic function, which may contribute to the ultimate development of HD symptoms.