To advance our understanding of autism spectrum disorder (ASD) and to develop novel therapeutics, it is critical to understand how genetic and cellular changes lead to changes in behavior and complex disease symptomatology. Genetically modified rats provide excellent substrate for this purpose, as rats cans perform complex behavior relevant to ASD; they are appropriate for large-scale, multi-site in vivo physiology while performing those behaviors; their behavior can be measured with large cohorts to support quantitative descriptions of group behavior; and they are also an appropriate system for slice physiology for precise mechanistic studies.

In the current project, the labs of Loren Frank, Kevin Bender and David Kastner will take advantage of all these strengths. The group will focus its efforts on Scn2a, a high-confidence ASD risk gene that encodes the neuronal voltage-gated sodium channel Na_V1.2. As people with ASD show deficits in spatial memory and navigation, the goal of this proposal is to describe the cellular, circuit and brain-wide changes with Scn2a haploinsufficiency that lead to dysfunctional spatial alternation learning, a learning paradigm that requires animals to learn to alternate between locations from a fixed starting position.

Frank, Bender and Kastner have created an integrated set of aims to study the effects of Scn2a haploinsufficiency within the hippocampus and prefrontal cortex, two critical brain regions for learning spatial alternation. The group will study these brain regions at three different levels of analysis: slice electrophysiology to determine the changes to cellular excitability, synaptic plasticity and signal propagation; in vivo electrophysiology to determine the changes to circuit-level communication within the hippocampus and between the hippocampus and prefrontal cortex; and brain lesions to determine the role of each brain region for the behavior and evaluate potential compensation between brain regions due to altered development and brain function. Each level of analysis will assist in the interpretation of the others, and for that purpose the group will also utilize computational modeling of the behavior to provide quantitative explanations to connect the different levels of analysis to task performance.