Investigating Cerebellar Mechanisms of Schizophrenia by Using a Pharmacological Mouse Model: Regulation of Voltage-Gated Potassium Channels

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 acute changes in behaviour induced by phencyclidine, and we introduce specific motor function tests to assess cerebellar involvement in the model. Together, these findings support several aspects of face, construct, and predictive validity expected of a schizophrenia model. Finally in Chapter 5 we investigate the cerebellar regulation of the three Kv subunits in our animal model, where we found Kv2.1 downregulation in the cerebellar cortex which is consistent with findings from human schizophrenia subjects and from animal studies. Strikingly, we found that the Kv6.4 is upregulated in several regions of the cerebellum that was supported by upregulated Kcng4 gene, which may indicate a compensatory mechanism for Kv2.1 loss. Additionally, we observed downregulation of the Kv3.1b in the granule cell layer of the right cerebellar lateral hemisphere, which may indicate a local functional demand. In conclusion, this thesis demonstrates, by using a range of behavioural, histological, and biomolecular investigations, the cerebellar pathology resulting from subchronic phencyclidine treatment, and also elucidates the functional role of Kv channels in a schizophrenia-like pathological state