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

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 d...

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Main Author: Guo, Lanboling
Other Authors: Albert I. Chen
Format: Theses and Dissertations
Language:English
Published: 2018
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Online Access:https://hdl.handle.net/10356/88408
http://hdl.handle.net/10220/45834
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-884082023-02-28T18:45:02Z Conditional deletion of cadherin-13 perturbs golgi cells in the cerebellum and disrupts social and cognitive behaviors Guo, Lanboling Albert I. Chen School of Biological Sciences DRNTU::Science::Biological sciences::Zoology::Animal behavior DRNTU::Science::Biological sciences::Molecular biology 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. Doctor of Philosophy 2018-09-05T06:29:37Z 2019-12-06T17:02:40Z 2018-09-05T06:29:37Z 2019-12-06T17:02:40Z 2018 Thesis Guo, L. (2018). Conditional deletion of cadherin-13 perturbs golgi cells in the cerebellum and disrupts social and cognitive behaviors. Doctoral thesis, Nanyang Technological University, Singapore. https://hdl.handle.net/10356/88408 http://hdl.handle.net/10220/45834 10.32657/10220/45834 en 126 p. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic DRNTU::Science::Biological sciences::Zoology::Animal behavior
DRNTU::Science::Biological sciences::Molecular biology
spellingShingle DRNTU::Science::Biological sciences::Zoology::Animal behavior
DRNTU::Science::Biological sciences::Molecular biology
Guo, Lanboling
Conditional deletion of cadherin-13 perturbs golgi cells in the cerebellum and disrupts social and cognitive behaviors
description 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.
author2 Albert I. Chen
author_facet Albert I. Chen
Guo, Lanboling
format Theses and Dissertations
author Guo, Lanboling
author_sort Guo, Lanboling
title Conditional deletion of cadherin-13 perturbs golgi cells in the cerebellum and disrupts social and cognitive behaviors
title_short Conditional deletion of cadherin-13 perturbs golgi cells in the cerebellum and disrupts social and cognitive behaviors
title_full Conditional deletion of cadherin-13 perturbs golgi cells in the cerebellum and disrupts social and cognitive behaviors
title_fullStr Conditional deletion of cadherin-13 perturbs golgi cells in the cerebellum and disrupts social and cognitive behaviors
title_full_unstemmed Conditional deletion of cadherin-13 perturbs golgi cells in the cerebellum and disrupts social and cognitive behaviors
title_sort conditional deletion of cadherin-13 perturbs golgi cells in the cerebellum and disrupts social and cognitive behaviors
publishDate 2018
url https://hdl.handle.net/10356/88408
http://hdl.handle.net/10220/45834
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