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Title: A mouse line for inducible and reversible silencing of specific neurons (Part I) ; The roles of Ulk4 on cerebral cortex development (Part II)
Author: Hu, Ling
ISNI:       0000 0004 6056 8802
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2016
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Part I abstract: Genetic methods for inducibly and reversibly inhibiting neuronal activity of specific neurons are critical for exploring the functions of neuronal circuits. The engineered human glycine receptor, called ivermectin (IVM)-gated silencing receptor (IVMR), has been shown to possess this ability in vitro, which abolish the binding with endogenous glycine and improve the sensitivity to ivermectin. Based on that, we constructed the knock-in plasmid which put IVMR in the downstream of a loxP-flanked STOP cassette. The Rosa26-IVMR mouse line was generated by inserting the plasmid into the Rosa26 locus though homologous recombination. IVMR expression can be induced by crossing with specific Cre mouse line or stereotactic injection of Cre-expressing virus. When expressing IVMR in unilateral striatal by injecting Cre-expressing virus, APO-induced rotation behavior was observed after inactivation of unilateral striatal neurons by administering ivermectin. Furthermore, 10mg/kg and 5mg/kg IVM are the effective ligand concentrations as they are able to induce obvious rotational behavior, but the effect last longer for 10mg/kg IVM than that for 5mg/kg. The physiological recording in vivo exhibited that neuron firing dramatically decreased in IVM-treated freely moving Rosa26-IVMR; Emx1-Cre mice and neuronal excitability in brain slice showed a substantial reduction as shown by increased threshold of the current needed to evoke the action potential and the reduced frequency of the action potential. In conclusion, our mouse line can inactivate the neuronal activity effectively in an inducible and reversible way with systemic administration of the ligand. So it provides a powerful tool for exploring selective circuit functions in freely behaving mice. Part II abstract: Schizophrenia is a chronic and severe mental disease which affects around 0.5%-1% population. However, the underlying cause are complex and remain unclear. Genetic abnormalities are considered to be the main risky factor. Although the typical symptoms start to occur between 18 and 30 age, the disturbance of neurodevelopmental process at earlier age is believed to be involved. To date, only a few of susceptibility genes are confirmed in human patients. Previously, through a meta-analysis of copy number variants (CNV) data from the International Schizophrenia Consortium and in vitro studies, we found a novel serine/threonine kinase gene, unc-51-like kinase 4 (Ulk4), as a risk factor for major mental disorders including schizophrenia. To investigate the Ulk4's roles in corticogenesis, Ulk4 knockout mice was employed. Though analyzing a series of developmental process during corticogenesis including laminar specification, neuronal migration in Ulk4 deficient mice, we found that Ulk4 loss led to the thinner layer II-IV, delayed neuronal migration and increased cell death in layer II-IV but did not affect the proliferation of progenitors which later give rise to the projection neurons in layer II-IV. Meantime the influence of Ulk4 deficiency on the deep layer (layer V and layer VI) development was limited. In conclusion, Ulk4 plays a crucial role on corticogenesis and regulates a variety of neurodevelopmental processes. When defective, this will lead to the increased risk of neurodevelopment disorders and also might be involved in the onset of mental disease including schizophrenia at early adolescence.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Neural circuitry ; Brain ; Schizophrenia ; Corticogenesis