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Assessing convergence in models of ASD: Physiology and behaviour in 16p11.2 deletion rats


About This PhD Project

Project Description

Project Code: 2020-SIDB-11

The 16p11.2. microdeletion in humans which leads to the loss of expression of approximately 21 genes occurs with a prevalence of about 3 in 10,000 individuals and is one of the most common copy number variants that gives rise to intellectual disability (ID) and autism spectrum disorder (ASD). Rodent models that mimic the 16p11.2 disorder have been created by deleting the syntenic regions in chromosomes 6 and 1 of mice and rats, respectively. One emerging theory in the study of neurodevelopmental disorders is that while there may a diversity of genetic bases that lead to ID/ASD it is hypothesized that there may be convergence in signalling pathways, neuronal circuits and networks that exhibit dysfunction in these disorders. Moreover, these pathophysiologies may manifest similar disrupted behaviours leading to the notion that common targets may exist for therapeutic intervention. Indeed our own work [1] has suggested that there is convergence of pathophysiology in rodent models of fragile X syndrome (FXS) and SYNGAP1 haploinsufficiency. Moreover, we have recently demonstrated that short-lasting drug intervention [2] can prevent the emergence of cellular and behavioural deficits in a rat model of FXS indicating that the underlying pathophysiology may be amenable to therapeutic intervention and is a deficit in neuro-maintenance rather than being an irreversible neurodevelopmental event. Of relevance to the study of 16p11.2 is the recent observation that a GABAB receptor antagonist, R-baclofen, which has shown some therapeutic potential in the treatment of FXS improves cognitive and social deficits in 16p11.2 mice [3]. This PhD project will offer the potential to take a multidisciplinary approach to the study of the pathophysiology in the rat 16p11.2 microdeletion model. Depending on an individual’s specific interests example studies could include biochemical analysis to assess protein homeostasis[1], electrophysiological analysis using both patch-clamp and extracellular recording to study synaptic function and plasticity[1, 4] and behavourial approaches[2, 4] to investigate episodic memory. All methodologies and approaches are routinely used in our labs and expert training in these will be provided. In addition, other SIDB investigators use pluripotent stem cell-derived neurons from 16p11.2 microdeletion individuals thus offering the potential, through collaboration, for electrophysiological analysis to be performed in a ‘human-based’ model system[5].

References

1. Barnes SA, Wijetunge LS, Jackson AD, Katsanevaki D, Osterweil EK, Komiyama NH, Grant SG, Bear MF, Nagerl UV, Kind PC et al: Convergence of Hippocampal Pathophysiology in Syngap+/- and Fmr1-/y Mice. J Neurosci 2015, 35(45):15073-15081.

2. Asiminas A, Jackson AD, Louros SR, Till SM, Spano T, Dando O, Bear MF, Chattarji S, Hardingham GE, Osterweil EK et al: Sustained correction of associative learning deficits after brief, early treatment in a rat model of Fragile X Syndrome. Sci Transl Med 2019, 11(494).

3. Stoppel LJ, Kazdoba TM, Schaffler MD, Preza AR, Heynen A, Crawley JN, Bear MF: R-Baclofen Reverses Cognitive Deficits and Improves Social Interactions in Two Lines of 16p11.2 Deletion Mice. Neuropsychopharmacology 2018, 43(3):513-524.

4. Till SM, Asiminas A, Jackson AD, Katsanevaki D, Barnes SA, Osterweil EK, Bear MF, Chattarji S, Wood ER, Wyllie DJ et al: Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS. Hum Mol Genet 2015, 24(21):5977-5984.

5. Livesey MR, Bilican B, Qiu J, Rzechorzek NM, Haghi G, Burr K, Hardingham GE, Chandran S, Wyllie DJ: Maturation of AMPAR composition and the GABAAR reversal potential in hPSC-derived cortical neurons. J Neurosci 2014, 34(11):4070-4075.

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