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Is the presynapse subject to an altered developmental trajectory in autism?

  • Full or part time
    Prof M Cousin
  • Application Deadline
    Sunday, January 12, 2020
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

About This PhD Project

Project Description

Project Code: 2020-SIDB-01

Synaptic transmission is dependent on the efficient and reliable coupling of neurotransmitter release to a spectrum of neuronal activity patterns. To ensure neurotransmission is maintained, the presynapse is organised to have 1) efficient coupling of calcium influx and synaptic vesicle (SV) fusion, 2) discrete functional pools of synaptic vesicles (SVs) and 3) a series of specific endocytosis modes from which new SVs are generated. In the first few months and years of life, the presynapse undergoes a number of functional and morphological changes during synapse establishment, stabilisation and maturity. Interestingly during the equivalent period in rodents, specific presynaptic parameters dramatically alter, including SV number, SV distribution between functional pools, coupling of SV fusion to calcium influx and SV biogenesis via endocytosis. We hypothesise that these key presynaptic changes are either delayed (or accelerated) during the critical period in autism, resulting in altered synapse formation, connectively and ultimately circuit function.

To test this hypothesis, we will employ a series of optical and morphological assays to monitor presynaptic function in primary neuronal cultures from a range of rat autism models. We will determine whether there is convergence in the delay of specific presynaptic parameters across these models. We will also attempt to correct these convergent phenotypes by molecular replacement of the mutated gene, and a series of molecular and pharmacological interventions that we have developed to alter presynaptic function. This project fits the core aims of SIDB, since it will 1) reveal novel mechanisms that potentially underlie autism, 2) define critical periods for therapeutic intervention and 3) potential convergence in common developmental mechanisms.

References

1. Baker K., Gordon S.L., Melland H., Bumbak F., Scott D.J., Jiang T.J., Owen D., Turner B.J., Boyd S.G., Rossi M., Al-Raqad M., Elpeleg O., Peck D., Mancini G.M.S., Wilke M., Zollino M., Marangi G., Weigand H., Borggraefe I., Haack T., Stark Z., Sadedin S; Broad Center for Mendelian Genomics, Tan T.Y., Jiang Y., Gibbs R.A., Ellingwood S., Amaral M., Kelley W., Kurian M.A., Cousin M.A., Raymond F.L. (2018) SYT1-associated neurodevelopmental disorder: a case series. Brain 141:2576-2591.

2. Kokotos A.C., Peltier, J. Davenport E.C., Trost M. and Cousin M.A. (2018) Activity-dependent bulk endocytosis proteome reveals a key role for the monomeric GTPase Rab11. Proc. Natl Acad Sci. 115:E10177-10186

3. Harper C.H., Mancini G.M.S., van Slegtenhorst M. And Cousin M.A. (2017) Altered synaptobrevin II trafficking in neurons expressing a synaptophysin mutation associated with a severe neurodevelopmental disorder. Neurobiol. Dis. 108: 298-306.

4. Nicholson-Fish J.C., Kokotos, A.C., Gillingwater T.G., Smillie K.J.* and Cousin M.A.* (2015) VAMP4 is an essential cargo molecule for activity-dependent bulk endocytosis. Neuron 88: 973-984.

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