[Abstract Title]. - Society for Neuroscience

Howard Hughes Medical Institute
Title: RNAi suppression of BDNF expression inhibits cortical plasticity
Authors: *J. T. PENA 1,3 , H. YAMAHACHI 2 , S. MARIK 2 , T. TUSCHL 2,4 , C. D. GILBERT 2 ;
1 Lab. of Neurobio., 2 Rockefeller Univ., New York City, NY; 3 Weill-Cornell Med. Col., New
York, NY; 4 Howard Hughes Med. Inst., New York, NY
Abstract: During the course of adult cortical plasticity, a number of signal transduction
mechanisms are brought into play. To study regulatory genes implicated in this process, we
inhibited gene expression by harnessing the machinery of RNA interference (RNAi) via small
hairpin RNAs (shRNA) delivered by viral vectors. Using this technology we sought to influence
plasticity of the mouse vibrissal barrel cortex. In this model system, chronic whisker plucking
reliably leads to the expansion of the cortical representation of the adjacent non-deprived
whiskers. The mechanism underlying this process involves changes in synaptic efficacy and
sprouting of axon collaterals. Initial studies describing the molecular events leading to
synaptogenesis and remapping have implicated a number of signal transduction pathways,
including neurotrophins such as brain derived neurotrophic factor (BDNF). Though previous
experiments have shown upregulation of neurotrophins and their receptors in reorganized cortex,
it is necessary to remove these factors to definitively prove their involvement in adult cortical
plasticity. We therefore repressed neurotrophic gene expression in the mouse somatosensory
cortex to determine if these trophic factors are essential for cortical remodeling after sensory
deprivation. We blocked gene expression in vivo using non-replicative adeno-associated virus
bearing genes encoding shRNA constructs. The shRNA nucleotide sequences were designed to
target and destroy selected neurotrophin messenger RNAs by triggering the RNAi pathway,
resulting in a reduction of BDNF protein levels by up to 80% in vivo. This knockdown of BDNF
expression effectively repressed functional cortical reorganization induced by chronic whisker
plucking. Manipulating gene expression via RNAi is therefore a useful approach towards
establishing the molecular link between sensory experience and use-dependent changes in
cortical circuits.
Disclosures: J.T. Pena, None; H. Yamahachi, None; S. Marik, None; T. Tuschl, alnylam, F.
Consultant/Advisory Board; C.D. Gilbert, None.
Poster
239. Structural Plasticity at Synapses I
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 239.11/E8
Topic: B.08.i. Structural plasticity