Olivia graduated from the University of Aberdeen with an Honours degree in Biomedical Science. Olivia completed her PhD in the University of Edinburgh, focusing on the mechanisms of peptide release from neuronal dendrites. After her PhD, Olivia moved in to the field of developmental biology to study FGF signalling in mesoderm cells during mesoderm migration and subsequent differentiation in Dr Arno Muller’s lab in the College of Life Sciences in the University of Dundee. In 2012 Olivia joined a project supervised by Prof. Lambert and Dr. Langston to investigate the effects of compounds designed to slow the progression of Huntington’s disease. This project is led by Prof. Schweiger (Dundee & Mainz).
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in exon 1 of the huntingtin gene resulting in an increased number of CAG repeats (>36), leading to aberrant huntingtin protein production and aggregation. HD is traditionally characterised and diagnosed by movement disturbances, however cognitive abnormalities often present prior to locomotor dysfunction and may occur, in part, through changes within the hippocampus [Lynch et al. (2007)]. The aim of this project is to develop in vitro cell and in vivo based assays for identifying effective candidate compounds for the treatment of HD.
The HdhQ111 mouse model
The HdhQ111 mouse model of HD [Wheeler et al (1999)] carries a replacement of mouse Hdh exon 1 with a chimeric Hdh:HD human exon1 with 111 CAG repeats. Olivia’s immunohistochemical studies revealed that mutant Huntingtin protein aggregate in neuronal cell nuclei at 6 month of age. These aggregations are most pronounced in the striatum including the nucleus accumbens. (Figure 1).
Cognitive deficits in the HD mouse model
At 1.5 months of age, wild type (WT) and heterozygous HdhQ111+/- mice can perform a simple novel object recognition (NOR) task with 24 hour delay between sample and test. However, by contrast to WT mice, by 3 months of age HdhQ111+/- mice cannot perform this task. In addition, HdhQ111/+ mice cannot perform an episodic-like memory task at 3 months of age, contrary to age-matched WT mice. Furthermore, our studies reveal hippocampal long term potentiation (LTP: an electrophysiological correlate of learning and memory) is impaired in HdhQ111+/- c.f WT) mice by 3 months. These phenotypes occur months before Htt aggregation in nuclei can be detected.
Characterisation of primary neuronal cultures produced from HdhQ111 mice are ongoing (Figure 2). These cultures allow cell-based assays to be developed suitable for identifying candidate compounds. One such assay in development is a fluorescent recovery after photobleaching (FRAP) assay. In this approach where neurons are transfected with exon1 of the htt gene fused to GFP. The recovery of the GFP fluorescent signal after photobleaching allows a determination of huntingtin protein synthesis and the influence of test compounds in real time.
Brain regions involved in the formation and retrieval of memories.
Unlike rats, the brain areas involved in the formation and retrieval of episodic-like memory in mice is unknown [Langston et al (2010); Wilson et al (2013)]. A transgenic mouse expressing GFP under the control of the immediate early gene promoter of fos is being used to map out brain areas activated after different memory tasks. With the help of a high content imaging system, a high through-put analysis of the whole brain can be achieved (Figure 3).
Lectures and conferences
Scottish Neuroscience Group meeting – Dundee 2012
Poster presentation: Cognitive deficits in the HdhQ111 mouse model of Huntington’s Disease: a role for ?5-GABAA receptors?
Scottish Neuroscience Group meeting – Edinburgh 2013
Oral presentation: Investigating the neural basis of recognition memory in the mouse hippocampus using a Fos-GFP mouse.
Poster presentation: Investigating the neural basis of recognition memory in the mouse hippocampus using a Fos-GFP mouse
Society for Neuroscience meeting – San Diego 2013
Poster presentation: Reversal of cognitive deficits in the HdhQ111 mouse model of Huntington’s disease by an ?5-GABAA receptor antagonist
Laboratory supervision of undergraduate Neuroscience BSc Honours and BMSc Honour’s projects.
Monteiro O, Wiegand UK, Ludwig M (2011) Vesicle degradation in dendrites of magnocellular neurones of the rat supraoptic nucleus. Neuroscience Letters 2011 Feb 1; 489 (1) 30 – 33.