Cdh11 Deficient Mice Exhibit Autism-like Behavioral Abnormalities

Background:  Genome-wide association studies and whole exome sequencing have shown that genetic variants of type II cadherins are associated with autism. However whether there is a causal relationship between cadherin deficiency and autism traits at behavioral and pathological levels remains to be clarified. The cerebellum or its input/output structure is among the most consistently-reported areas of vulnerability in autism, as evidenced by cellular and functional pathology. Individuals with ASD exhibit deficits in motor control in addition to core autism symptoms such as difficulties in language and social interaction. Our preliminary results show extensive expression of cadherins in the cerebellum. However the role of cadherins in the development and function of cerebellar circuities is not well understood.

Objectives:  The Cadherin-11 gene knockout (KO) mouse was used as a model system to elucidate the behavioral impact of cadherin deficiency and the underlying brain developmental mechanisms, with a focus on pathological changes in the cerebellum.

Methods:  In-situ hybridization was used to reveal the expression of Cadherin-11 in developing brain. Immunofluorescence staining of sagittal and coronal brain sections was applied for histological analysis of the Cadherin-11 KO mouse. Standard open field test, elevated plus maze, and 3-chamber social preference test were carried out to evaluate autism-like behaviors. Gripping strength test, horizontal bar test, rotarod test, and footprint analysis were performed to evaluate the motor function of the animal.

Results:  In the developing mouse brain, Cadherin-11 is expressed in structures that are known to be closely relevant to autism, including the cerebellum and in the inferior olivary nucleus, which projects to the cerebellum. Compared to wild type (WT) littermates, most Cadherin-11 KO mice showed reduced brain sizes, including the cerebral cortex and the cerebellum. In the cerebellum, the lobes failed to fold to the mature pattern. This developmental deficit appeared to occur postnatally as the brain sizes were largely unaffected when examined at E18.5. Both male and female Cadherin-11 mutant mice are hyperactive, as reflected by a significantly elevated time to explore the central area of the open field arena compared to WT littermates. In an elevated plus maze test, mutant mice spent significantly less time in the open arm, indicating elevated anxiety levels. Consistent with deficits in cerebellum-related motor coordination, mutant mice also exhibited significantly lower scores in the gripping strength test and horizontal bar test and showed abnormal gait pattern in foot print analysis. The 3-chamber social preference test, however, showed that Cadherin-11 mutant mice were not severely impaired in social interactions.

Conclusions:  Cadherin-11 is required for the development of some specific brain functions which are altered in autism. Loss-of-function of a single autism risk gene, Cadherin-11, in mice is sufficient to generate several important aspects of the autism-like behavior abnormalities (hyperactivity, high anxiety, and motor deficits) potentially by affecting cerebellar function. Cadherin-11 gene knockout mice may serve as a novel animal model to further dissect the mechanisms of olivocerebellar circuit changes in autism.