[Abstract Title]. - Society for Neuroscience

polarization assay. The screen yielded several compounds with affinities in the low micromolar
range. One compound (231) with desirable chemical properties was selected for further detailed
characterization. Its interaction with the PICK1 PDZ domain was confirmed using a GST pulldown
assay showing dose-dependent and reversible inhibition of the interaction between the
DAT C-terminus and PICK1. According to both pull-down experiments and a fluorescence
polarization assay, compound 231 displayed no affinity towards the three PDZ domains of
PDS95. Molecular modeling and mutagenesis support that compound 231 bind in the binding
groove of the PICK1 PDZ domain. Using a FRET setup, the compound was shown to inhibit the
PICK1 - GluR2 interaction in living cells thereby demonstrating its membrane permeability.
Moreover, compound 231 was shown to block LTD in CA1 pyramidal cells with similar efficacy
as C-terminal peptides corresponding to the GluR2 C-terminus, Analogues of compound 231 are
currently being synthesized to optimize affinity.
Disclosures: T.S. Thorsen, None; K. Madsen, None; N. Rebola, None; A. Bach, None; T.
Beuming, None; N. Stuhr-Hansen, None; D. Peters, Neurosearch A/S, A. Employment (full or
part-time); T. Dyhring, Neurosearch A/S, A. Employment (full or part-time); H. Weinstein,
None; K. Strømgaard, None; C. Mulle, None; L. Rønn, Neurosearch A/S, A. Employment (full
or part-time); U. Gether, None; I. Moreira, None.
Poster
238. LTD: Hippocampus and Cortex
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 238.13/D58
Topic: B.08.f. Long-term depression ( LTD )
Support: Medical Research Council (UK)
The Wellcome Trust
BBSRC
Title: Tyrosine dephosphorylation of GluR2 regulates AMPAR internalisation in mGluR-LTD
but not in NMDAR-LTD
Authors: *E. MOLNAR, C. M. GLADDING, Z. I. BASHIR, G. L. COLLINGRIDGE;
MRC Ctr. Synaptic Plasticity, Univ. Bristol, Bristol, United Kingdom
Abstract: Long-term depression (LTD) can be induced at hippocampal CA1 synapses, by
activation of either NMDA receptors (NMDARs) or group I metabotropic glutamate receptors