Our central hypothesis is that developmental delay syndromes including autism spectrum disorders lead to alterations in synaptic function in integrative brain regions that result in aberrant behavioral phenotypes. We will explore this hypothesis in a genetically modified rat model. Haploinsufficiency of SHANK3 leads to neurodevelopmental changes that include autism spectrum disorders, attentional disorders, absent or delayed speech, mild to moderate intellectual disability, and motor alterations. The SHANK3 protein forms a key structural part of the postsynaptic density. Because of the closer physiology between rats and humans as compared to mice, rats remain the primary choice of the pharmaceutical industry for studying pharmacokinetic (PK) properties of novel drugs. In addition, rats provide a far more tractable experimental model system for neurobiological, electrophysiological and behavioral studies, and it is of course advantageous, when considering drug development, that the biological assays be done in the same species where the PK studies are carried out. We have used zinc-finger nucleases to develop a genetically engineered rat with a disruption in the full-length rat Shank3 gene. This represents a first-ever genetically modified rat model for ASD and permits us to carry out detail studies in the prefrontal cortex, an area of great importance in autism, not easily studied in mouse models. We propose to carry out a detailed analysis of this model. We plan to test our central hypothesis with the following specific aims: 1) Behavioral assessment of prefrontal function in Shank3-deficient rats; 2) Electrophysiological analysis of prefrontal function in Shank3-deficient rats; and, 3) Neuropathological and neurochemical investigation of prefrontal function in Shank3-deficient rats. 3) The research is innovative, in our opinion, because it will make use of a first-ever rat model of ASD. In addition, it is innovative in the use of state-of-the art approaches to understanding the role of PFC in ASD, a key region not yet studied in detail in ASD model systems. The focus on PFC also allows for studying neuronal pathways that feed into the PFC, including the first-ever behavioral neurophysiological assessment of hippocampal-prefrontal circuitry in a rodent model for ASD. Our approach to high-resolution 3D imaging and analysis of neuronal morphology down to the level of single spine is notably novel. This form of analysis will allow us to identify molecular targets that are affected in Shank3-deficient rats, in particular, te distribution of excitatory receptors and synaptic proteins known to be linked to spine and synapse size and maturity. Finally, our behavioral analyses will make use of novel touchscreen chambers for detailed analysis of PFC function.
The proposed research is relevant to public health and to the NIH mission because the studies will lead to a molecular and systems level understanding of Shank3 function and will identify molecular targets for novel therapeutics in developmental delay and ASD using a first genetically modified rat model for ASD. Rats are an ideal model to examine the prefrontal cortex, which has been strongly implicated in ASD. A first rat model is also relevant to the NIH mission.
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