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The Journal of Neuroscience, July 26, 2006, 26(30):7820-7825; doi:10.1523/JNEUROSCI.1957-06.2006

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Brief Communications
Retraction of Synapses and Dendritic Spines Induced by Off-Target Effects of RNA Interference

Veronica A. Alvarez, Dennis A. Ridenour, and Bernardo L. Sabatini

Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Bernardo L. Sabatini, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115. bsabatini{at}hms.harvard.edu

RNA interference (RNAi), which allows selective gene silencing, has been proposed for functional genomic analysis and for the treatment of human disease. However, induction of RNAi in mammalian cells by expression of double-stranded RNA can activate innate antiviral response pathways that perturb off-target gene expression. The activation and functional consequences of these effects in neurons are unknown. We find that expression of subsets of short hairpin RNAs (shRNAs) in rat hippocampal pyramidal neurons can have off-target effects that reduce the complexity of dendritic arbors and trigger the loss of dendritic spines. Morphological changes are accompanied by electrophysiological perturbations in passive membrane properties and a decrease in the number and strength of excitatory and inhibitory synapses. These perturbations depend on the shRNA sequence and are independent of the identity of the targeted protein. Our results indicate that off-target effects of RNAi severely perturb neuronal structure and function and may lead to the functional withdrawal of affected cells from the brain circuitry.

Key words: RNA interference; short hairpin RNA; interferon response; synaptic transmission; dendritic spine; off-target effects

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Received May 8, 2006; revised June 15, 2006; accepted June 18, 2006.

Correspondence should be addressed to Bernardo L. Sabatini, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115. bsabatini{at}hms.harvard.edu

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