Serial two-photon tomography-based whole-brain activity mapping in cntnap2 ko mouse model of autism

Autism is a highly heritable neurodevelopmental disorder, affecting about 1% of children. Based on the identification of candidate genes for autism, genetic mouse models have been developed, allowing for targeted studies of gene-to-brain interactions that may underlie neurodevelopmental changes in individuals with autism. Several genetic mouse models were found to exhibit autism-related phenotypes, including Cntnap2 knockout (KO) mice that have been shown to recapitulate some autism-related behaviors, including impaired social interaction. Here, we mapped brain circuit activation during social behavior in the Cntnap2 KO mouse model. First, we independently repeated and validated the impaired social behavior phenotype in the Cntnap2 KO mice (Peñagarikano et al., 2011). To investigate the brain mechanisms of the impaired social behavior in the Cntnap2 KO mice, we used serial two-photon (STP) tomography-based mapping of whole brain activity. STP tomography images the entire mouse brain at cellular resolution with near complete 3D reconstruction (Ragan et al., 2012). We used immediate early gene c-fos, a molecular marker of neuronal activation, to visualize brain activation by STP tomography in transgenic c-fos-GFP mice crossed with Cntnap2 KO mice. The c-fos-GFP datasets were processed by computational methods that detect the activated GFP-positive neurons, warp their distribution to a reference brain registered to the Allen Mouse Brain Atlas, and identify activated brain regions by statistical tests in the c-fos-GFP+Cntnap2 KO and c-fos-GFP+Cntnap2 wild type (WT) littermates. We compared three groups of male mice in each genotype: 1) a home-cage baseline group (no experimental manipulation), 2) an object group (a novel object added to the home cage for 90 seconds), and 3) a social group (an ovariectomized Cntnap2 heterozygote female added to the home cage for 90 seconds). Preliminary results suggest that fewer brain regions become significantly activated in the KO compared to the WT mice during social behavior. In contrast, more brain regions are activated in the KO compared to the WT mice during novel object exploration. Our current hypothesis is that the loss of Cntnap2 affects selectively brain circuitry related to social processing