Prefrontal Circuitry Deficits in a Novel Shank3-Deficient Rat

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.