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Title: Molecular mechanisms of neuronal homoeostasis in vivo
Author: Seo, Sang soo
ISNI:       0000 0004 6499 9917
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2016
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Homeostatic plasticity is important in neurobiology for stabilising neuronal networks in the face of Hebbian forms of synaptic plasticity that are thought to mediate memory storage. Impairment of homeostatic plasticity has also been implicated in neurological diseases such as Rett syndrome and fragile X syndrome. Homeostatic plasticity can be achieved through scaling of the strength of synaptic connections between neurones or by changes in intrinsic excitability. While homeostatic plasticity has been studied mainly using in vitro preparations, it is for the most part not known whether changes of neural activity in vivo induce homeostatic changes. The molecular pathway responsible for homeostatic plasticity still remains unclear. In this thesis, I have used stereotaxic surgery to over express Kir2.1, an inwardly rectifying potassium channel, in vivo in the brains of adult mice. I show that the expression of Kir2.1 through adeno-associated virus (AAV) does not cause any adverse effects in the dentate gyrus nor the CA1 of the mouse hippocampus. I go on to use slice patch clamp methods to measure the change in electrical properties of granule cells in the dentate gyrus and pyramidal cells in CA1 caused by expression of Kir2.1. I show that the excitability of neurones expressing Kir2.1 was reduced compared to control neurones. By 2 weeks after virus injection the neurones showed homeostatic plasticity in response to Kir2.1 over expression. Interestingly, the mechanism of adaptation was different in different types of cells; dentate gyrus granule cells adapted through change in their intrinsic excitability, whereas CA1 pyramidal cells adapted by modifying the strength of their synaptic inputs. To establish whether induction of homeostatic plasticity is associated with changes in gene expression I used fluorescent activated cell sorting (FACs) to isolate pure population of neurones infected with viruses. I then sequenced RNA extracted from neurones expressing Kir2.1 and control neurones. Analysis of the RNAseq data revealed molecular candidates involved in homeostatic plasticity. In summary, I show that Kir2.1 over expression causes change in excitability and subsequent homeostatic plasticity in vivo. The mechanism of adaptation differs between cell types. RNAseq results identify novel candidates for future investigation.
Supervisor: Nolan, Matthew ; Hardingham, Giles Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: fluorescent activated cell sorting ; FACs ; RNAseq ; homeostasis ; hippocampus