| Abstract No.: | C-B3067 |
| Country: | Canada |
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| Title: | ADENOMATOUS POLYPOSIS COLI (APC) PROMOTES MATURATION OF DENDRITIC SPINES AND FUNCTIONAL SYNAPSE FORMATION IN THE MEDIAL PREFRONTAL CORTEX |
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| Authors/Affiliations: | 1 Jonathan Lai*; 1 John Armstrong;
1 University of Guelph, Molecular Neurobiology Laboratory, Department of Biomedical Sciences, ON, Canada
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| Content: | Adenomatous polyposis coli (APC) is an important signaling molecule in the Wnt signaling pathway. APC negatively regulates Wtn signaling by binding to GSK3β and axin, facilitating GSK3β-mediated phosphorylation of β-catenin and promoting its proteosome-dependent degradation rather than its cytoplasmic and nuclear accumulation. APC mRNA is highly expressed in the central nervous system during late embryological and early postnatal development. However, very little is known about its role in development of the nervous system. Two recent reports suggest that APC may play an important role in the development of dendrites by regulating microtubule assembly, actin dynamics and the clustering of postsynaptic receptors during synaptogenesis.
Objectives: The objectives of this study were to determine the effects of the APC signaling mutation APCmin on dendritic spine density, morphology and functional synapse formation in pyramidal cells of the medial prefrontal cortex (mPFC). Heterozygous, APCmin mice possess a single point mutation on the APC gene that results in truncation of the polypeptide and elimination of several important C-terminal signaling domains. Materials and Methods: Golgi-Cox staining was carried out on the brains of 2 week old male wildttype C57BL/6J and APCmin /J mice. Pyramidal cells in layers III and V were examined and spine density and length were measured on distal, proximal and basilar dendrites. Funtional synapse formation was measured using IR-DIC patch clamp recordings in acute mPFC slices of 2 week old male C57BL/6J and APCmin /J mice. Whole cell voltage clamp recordings were carried out and the frequency (interevent interval) and amplitude of AMPA-receptor mediated miniature EPSCs (mEPSCs) were recorded in 10µM bicuculline, 50µM picrotoxin and 1µM tetrodotoxin.
Results: Pyramidal neurons of APCmin mice had significantly longer basilar and proximal dendritic spines than neurons from wildtype mice. This was particularly apparent in the layer V pyramidal cells of the main dendritic shaft between 25-50% of its length. However, no statistical differences in spine density were apparent between wildtype and APCmin mice in any of the 3 areas examined. Consistent with the results of dendritic spine analysis suggesting longer more immature dendritic spines in the mPFC of APCmin mice, recordings from pyramidal cells of APCmin mice exhibited a lower frequency of mEPSCs and longer interevent intervals. The amplitude of AMPA-receptor mediated mEPSCs was also significantly greater than those recorded in wildtype mice. Work is currently being carried out to determine is this increased amplitude in APCmin neurons is the result of decreased trafficking of GluR2. Conclusion: APC plays an important role in dendrites by promoting the maturation of dendritic spines and contributing to functional synapse formation in the medial prefrontal cortex.
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