Investigating Cerebellar Mechanisms of Schizophrenia by Using a Pharmacological Mouse Model: Regulation of Voltage-Gated Potassium Channels
type: CreativeWork
description: Schizophrenia is a heterogeneous psychiatric disorder which affects at least 1% of the global population. Its complex pathology involves impaired neuronal communication that leads to the onset of debilitating symptoms affecting behaviour and cognition. Voltage-gated potassium (Kv) channels are fundamental to neuronal communication because of their intricate roles in regulating neuronal excitability, thereby governing information processing in the brain. The cerebellum has a significant influence over how this information is communicated across the brain because of its interconnectivity with virtually all brain regions. To expand our understanding of Kv channels, this thesis investigates the regulation of three alpha subunits of voltage-gated potassium channels Kv2.1, Kv6.4, and Kv3.1b in the cerebellar cortex of a phencyclidine-induced mouse model of schizophrenia and explores their potential role in schizophrenia symptoms. In Chapter 3 we show using immunohistochemistry that Kv2.1 is expressed in the Purkinje cells and granule cells as membrane-bound clusters in the soma and proximal dendrites, whereas the Kv6.4 are mainly present in the cytosol. Additionally, using proximity ligation we demonstrated for the first time that Kv6.4 arrange with Kv2.1 to form heteromeric channels on the perisomatic membrane of Purkinje cells. These findings suggest that Kv2.1 and Kv6.4 may act as neuronal ‘transistors’ thereby controlling the frequency of neuronal firing in these cell populations. In Chapter 4 we describe the behavioural phenotype of our CBA/CA phencyclidine model to include altered exploratory patterns, changes in locomotor activity, and changes in rearing and grooming behaviours. We also observed dysregulation of NMDA-receptor genes in frontal cortex and the cerebellum, and abnormalities in several features of the cerebellum of the model mice. Additionally, we describe the effectiveness of concomitant antipsychotic agents haloperidol and clozapine in attenuating the…
abstract: Schizophrenia is a heterogeneous psychiatric disorder which affects at least 1% of the global population. Its complex pathology involves impaired neuronal communication that leads to the onset of debilitating symptoms affecting behaviour and cognition. Voltage-gated potassium (Kv) channels are fundamental to neuronal communication because of their intricate roles in regulating neuronal excitability, thereby governing information processing in the brain. The cerebellum has a significant influence over how this information is communicated across the brain because of its interconnectivity with virtually all brain regions. To expand our understanding of Kv channels, this thesis investigates the regulation of three alpha subunits of voltage-gated potassium channels Kv2.1, Kv6.4, and Kv3.1b in the cerebellar cortex of a phencyclidine-induced mouse model of schizophrenia and explores their potential role in schizophrenia symptoms. In Chapter 3 we show using immunohistochemistry that Kv2.1 is expressed in the Purkinje cells and granule cells as membrane-bound clusters in the soma and proximal dendrites, whereas the Kv6.4 are mainly present in the cytosol. Additionally, using proximity ligation we demonstrated for the first time that Kv6.4 arrange with Kv2.1 to form heteromeric channels on the perisomatic membrane of Purkinje cells. These findings suggest that Kv2.1 and Kv6.4 may act as neuronal ‘transistors’ thereby controlling the frequency of neuronal firing in these cell populations. In Chapter 4 we describe the behavioural phenotype of our CBA/CA phencyclidine model to include altered exploratory patterns, changes in locomotor activity, and changes in rearing and grooming behaviours. We also observed dysregulation of NMDA-receptor genes in frontal cortex and the cerebellum, and abnormalities in several features of the cerebellum of the model mice. Additionally, we describe the effectiveness of concomitant antipsychotic agents haloperidol and clozapine in attenuating the…
author: Lagojda, Lukasz
license: https://dora.dmu.ac.uk/bitstreams/13cef712-b0d5-49f4-86d4-899547421fb9/download
date published: 2021-10
date modified: 2026-07-24T06:18:37Z
provider: De Montfort University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: De Montfort University