One of the fundamental questions driving research at the Allen Institute is how cortical circuitry underlies complex brain function. Understanding the cellular and molecular structure of these circuits is the first step but it is also important to understand how disturbances in these circuits influence function. One way to approach this is to examine differences that exist normal mice and those with impaired cortical functioning. Two human diseases that are associated with profound disruption of cognitive and emotional function are schizophrenia and autism. Schizophrenia is a chronic, disabling, neurological disorder. It is associated with disturbances in sensory perception (including hallucinations and delusion), impaired working or procedural memory, disorganized thoughts, and flattened affect. Autism is a developmental disorder that causes severe and pervasive impairment in cognitive flexibility, interpretation of feelings, language, the ability to relate to others, and atypical perception of somatosensory, visual, auditory, gustatory, and olfactory signals. Both of these disorders have been linked to defects in cortical development. Better classification of the changes in cortical connectivity that are associated with these diseases will lead to increased understanding of the correlation between structure and function. Since tissue from human patients is hard to obtain we will begin to address this question using animal models of schizophrenia and autism.
In order to assess structural defects in these mouse models we have identified molecular markers that specifically delineate subregions of the cortex, hippocampus and amygdala. These markers provide powerful tools for analysis of the fine cellular architecture of these structures, as well as a means to assess disorganization of normal brain architecture. 

An example of the power of molecular phenotyping to identify and characterize disorganized cellular architecture is shown in Figure 1, a panel of cortical layer-specific genes was used to characterize the laminar architecture of the neocortex in Reelin knockout mice.  Mice homozygous for the reeler (Relnrl) mutation exhibit an ataxic gait, dystonic posture and tremors starting around 2 weeks of age. This mouse has been extensively described as having inverted cortical layers due to a migration defect during migration of newly generated cortical neurons from the ventricular zone into the developing cortex.  The marker panel clearly shows cellular disorganization, but further demonstrates a more fundamental disorganization than simple inversion.  Application of these marker panels should reveal more subtle cellular abnormalities in mouse models of autistic spectrum disorders that are difficult to identify using conventional techniques.