Characterisation of a mouse model of Protocadherin 19

The protocadherin 19 (PCDH19) gene is encoded on the X-chromosome and its mutation causes Early Infantile Epileptic Encephalopathy 9 (EIEE9). This disorder is characterised by epilepsy in infancy or early childhood, often accompanied by cognitive impairment and behavioural disturbances of diverse severity in heterozygous females. Mosaicism of PCDH19 positive and negative cells is believed to underpin the symptoms through a mechanism of cellular interference, leading to disruption in cell-cell communication, synapse formation and hyperexcitability of neurons. However, the expression and function of the gene in mammals are still poorly understood. The aim of this thesis was to characterise a Pcdh19-knock-out (KO) mouse model, focusing on cortical migration and lamination, and on animal behaviour. An analysis of the neuronal types expressing Pcdh19 in the postnatal cortex was also undertaken. By combining RNA in situ hybridisation and immunohistochemistry, Pcdh19 was found to be expressed by a wide variety of excitatory and inhibitory neuronal types, although expression was strongest in layers II/III and Va. In utero electroporation experiments in mutant animals revealed subtle differences in the migration of Pcdh19-KO neurons but no significant changes in Pcdh19 heterozygous (HET) females. Accordingly, analysis of cortical markers by immunostaining revealed only very minor differences in the number or distribution of marker-positive cells between Pcdh19-WT and mutant animals. The results of the behavioural analysis suggested a higher sensitivity of Pcdh19-HET females to new environments and demonstrated an effect of housing on the behaviour of WT animals. Together, this study highlights the heterogeneity of Pcdh19 expressing cells and discards major roles of this protein in cortical lamination and migration. However, the behavioural changes point to alterations in circuit formation or function. These results provide an initial path to gain insight into the pathophysiology of EIEE9