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Prefrontal Circuitry Deficits in a Novel Shank3-Deficient Rat

Friday, 3 May 2013: 14:15
Chamber Hall (Kursaal Centre)
J. D. Buxbaum1,2, M. G. Baxter3, O. B. Gunal1, H. Harony-Nicolas1, P. R. Hof3, D. Papapetrou3, N. Uppal3 and F. J. Yuk3, (1)Psychiatry, Mount Sinai School of Medicine, New York, NY, (2)Seaver Autism Center for Research and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, (3)Neuroscience, Mount Sinai School of Medicine, New York, NY
Background:  SHANK3 is a critical protein in the postsynaptic density (PSD), which interacts with many synaptic proteins and cytoskeletal elements. Loss of a functional copy of the SHANK3 gene leads to a monogenic form of an autism spectrum disorder (ASD) called Phelan-McDermid Syndrome (PMS). There is good evidence for prefrontal deficits in SHANK3 deficiency and in ASD. Shank3-deficient mouse models, exhibit synaptic dysfunction and behavioral deficits relevant to symptoms of ASD but are not an ideal model for parsing neural circuitry, especially the prefrontal cortex.

Objectives:  To further analyze the effect of Shank3 deficiency on neural pathways in brain regions related to ASD symptoms.

Methods:  We developed a genetically modified rat model with a targeted disruption of Shank3, choosing a region of the gene relevant to human mutations. We are applying biochemical, electrophysiological, genome wide transcriptional analysis and behavioral studies to reveal changes due to Shank3-deficiency.

Results:  We observe reduced levels of Homer and PSD-95 in the hippocampus and medial prefrontal cortex in Shank3-deficient rats. Our results also revealed that reduced levels of Shank3 lead to deficits in hippocampal long-term potentiation (LTP) and long-term depression. Furthermore LTP in the hippocampal-medial prefrontal pathway, analyzed using in vivo recordings of field excitatory responses, was also impaired in Shank3-deficient rats. Finally, Shank3-deficient rats showed a specific working memory deficit.

Conclusions:  By further characterizing this rat model we will be able to reveal disrupted pathways that would then be targets for developing novel therapeutics for PMS and ASD.

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