Use this URL to cite or link to this record in EThOS:
Title: The role of X-linked cell adhesion molecule protocadherin 19 in neurogenesis and synapse formation
Author: Griffiths, Jessica
ISNI:       0000 0004 7962 1992
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2019
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Restricted access.
Access from Institution:
Mutations in X-linked protocadherin 19 (PCDH19) lead to EIEE9 (Early Infantile Epileptic Encephalopathy 9), a syndrome characterised by early-onset epilepsy and cognitive impairment. PCDH19 tissue mosaicism is thought to be a critical driver of the disorder as the coexistence of PCDH19-expressing and non-expressing cells is believed to disrupt cell-cell communication, leading to hyperexcitability of neurons and the epileptic phenotype. The early-onset of the disorder and the spatiotemporal expression of Pcdh19 in the developing cortex suggests a role for PCDH19 in cortical neurogenesis and synapse formation. Those two processes were therefore investigated in this thesis. Firstly, during corticogenesis, Pcdh19 expression was found to be complementary to the neurogenic gradient. Expression was high in RGC progenitors and declined in IPCs. Remarkably, PCDH19-expressing and non-expressing progenitors segregated in the cortex of Pcdh19 HET mice, leading to an unusual phenomenon. Although cell cycle parameters, progenitor cell numbers, and neuronal output did not differ between PCDH19-expressing and non-expressing progenitors in WT and KO cortices, within the HET cortex, these progenitors had opposing neurogenic properties, producing significantly less and more neurons, respectively. Interestingly, these opposed behaviours resulted in a lack of differences overall between genotypes, suggesting a potential regulatory mechanism. PCDH19's role in synaptogenesis was assessed in ESC-derived "cortical-like" neurons. A co-culture system of WT and KO neurons was generated to study PCDH19 mosaicism in vitro. No overall differences were found in the number of synapses formed; however, a preliminary assessment of spontaneous neuronal activity and calcium handling indicated that KO and co-cultured neurons had altered excitability and KCl-evoked calcium responses. Together, this study shows that the co-existence of PCDH19-expressing and non-expressing cells affects cortical development. The in vivo and in vitro approaches developed in this thesis will help decipher the cellular and molecular mechanisms that govern these behaviours, to help understand the pathophysiology of EIEE9.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Q Science (General) ; RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry