Neuropathology and animal models of autism: genetic and environmental factors

Abstract

Autism is a heterogeneous behaviorally defined neurodevelopmental disorder. It is defined by the presence of marked social deficits, specific language abnormalities, and stereotyped repetitive patterns of behavior. Because of the variability in the behavioral phenotype of the disorder among patients, the term autism spectrum disorder has been established. In the first part of this review, we provide an overview of neuropathological findings from studies of autism postmortem brains and identify the cerebellum as one of the key brain regions that can play a role in the autism phenotype. We review research findings that indicate possible links between the environment and autism including the role of mercury and immune-related factors. Because both genes and environment can alter the structure of the developing brain in different ways, it is not surprising that there is heterogeneity in the behavioral and neuropathological phenotypes of autism spectrum disorders. Finally, we describe animal models of autism that occur following insertion of different autism-related genes and exposure to environmental factors, highlighting those models which exhibit both autism-like behavior and neuropathology.

Figure 1

Symptoms of autism as per DSM-IV criteria. The core symptoms of autism are related to speech and language problems, stereotyped and repetitive behaviors, and social impairment. Other symptoms often associated with ASDs are epilepsy and mental retardation.

Figure 2

The cerebellum projects to motor and nonmotor regions in the monkey brain. Targets of cerebellar output, indicated in red, are areas of the cerebral cortex that have motor-related functions. Blue labels indicate cortical areas that are the nonmotor targets of cerebellar output. The areas are indicated on the lateral aspect of the Cebus monkey brain. The numbers 9 and 46 refer to cytoarchitectonic areas of the prefrontal cortex. AS: arcuate sulcus; FEF: frontal eye field; LS: lateral sulcus; M1: areas of the primary motor cortex; PMd: dorsal premotor area; PMv: ventral premotor area; PrePMd: predorsal premotor area; ST: superior temporal sulcus. Modified from Strick et al. [20].

Figure 3

Environmental and genetic factors play a role in autism and altering the immune system. Environmental factors, like valproic acid, thalidomide, and thimerosal-containing vaccines, play a role in causing neurodevelopmental disorders and altering immune system function in humans with autism and in animal models of autism. Genetic mutations in MeCp2, TSC, and Reelin can induce an autism phenotype as well as autism-like neuropathology and/or immune system impairment when inserted into mice. The “?” indicates missing evidence for TSC and Reelin causing immune system alterations.