Conditional deletion of cadherin-13 perturbs golgi cells in the cerebellum and disrupts social and cognitive behaviors

• Main Author: Guo, Lanboling
• Other Authors: Albert I. Chen
• Format: Theses and Dissertations
• Language: English
• Published: 2018
• Subjects: DRNTU::Science::Biological sciences::Zoology::Animal behavior; DRNTU::Science::Biological sciences::Molecular biology
• Online Access: https://hdl.handle.net/10356/88408; http://hdl.handle.net/10220/45834
• Institution: Nanyang Technological University

The cerebellum plays important roles in motor coordination and motor learning. In addition to motor-related functions, the cognitive functions and social behaviors in humans, non-human primates and rodents have been linked to the cerebellum. Cognitive and social behavioral impairments have been described in patients who have suffered damages in the cerebellum. Functional brain imaging studies also provide evidence for the contribution of the cerebellum to cognitive and social-related function. Even though Purkinje cells, the primary projection neurons in the cerebellar cortex, have been linked to non-motor function of the cerebellum, relatively little studies have focused on the role of cerebellar interneurons in cognitive and social behaviors. Cadherin-13 is classified as a member of cadherin superfamily but its function is diverse in different systems. GWAS studies have reported the link between Cadherin-13 to social and cognitive behavioral impairment-related neurological disorders including autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD) and schizophrenia. We found that Cdh13 is expressed specifically in the internal granular layer (IGL) inhibitory neurons in the cerebellar cortex. To explore the role of Cdh13 and study the function of the cerebellum through manipulation of the expression of Cdh13, we generated Cdh13 conditional knockout mice mediated by GlyT2::Cre in which Cdh13 was ablated in the cerebellum and piriform cortex. Ablation of Cdh13 in neurons in these regions results in a decrease of the expression of GAD67 or a change of GAD67 localization suggesting the involvement of Cdh13 in maintenance or regulation of the normal function or development of inhibitory synapses. In addition, the inhibitory inputs on Golgi cells reduced in Cdh13 condition mutant mice support the contribution of Cdh13 to the function or development of inhibitory neurons that form synapses onto Golgi cells. At the behavioral level, loss of Cdh13 does not affect general motor coordination or locomotor behaviors, but results in impairments in cognitive flexibility and social interactions. Mice lacking Cdh13 mediated by GlyT2::Cre show cognitive flexibility deficits and disrupted social contact pattern concomitant with increase of reciprocal social interactions. Overall, our findings indicate that Cdh13 is important for inhibitory circuit of the cerebellar cortex and that genetic manipulation in GABAergic neurons in non-executive centers of the brain, such as the cerebellum, may contribute to neurological disorders related cognitive and social behavioral impairments.