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CDKL5’s role in neuronal homeostatic plasticity

  • Full or part time
    Dr S Ultanir
    Dr J Burrone
  • Application Deadline
    Tuesday, November 12, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

A joint Crick-King’s College London funded PhD position for the 2019 programme between the labs of Sila Ultanir and Juan Burrone.

CDKL5 is a serine/threonine kinase that has a kinase domain similar to other CDKLs (1-4), as well as MAP, GSK, CDK family of kinases. Loss of function mutations of CDKL5 cause a neurodevelopmental disorder with seizures and severe developmental problems. This rare monogenic disorder is now termed CDKL5 Deficiency Disorder (CDD). Although CDD is a very severe disorder, CDKL5 knockout mice develop largely normally and do not display seizures. Using chemical genetic substrate phosphorylation analysis, Ultanir lab determined direct substrates of CDKL5 and showed that CDKL5 alters microtubule dynamics via phosphorylating microtubule binding proteins [1]. Functional consequences of these signaling perturbations on microtubule cytoskeleton remain elusive.

We propose first to conduct a detailed morphological characterization of the dendritic structure of hippocampal pyramidal neurons, which express high levels of CDKL5. Basal, apical trunk, apical oblique branches and apical tuft will be investigated separately. In addition, we will use genetically-encoded reporters (fibronectin intrabodies, [2] of excitatory and inhibitory synapse location to provide cell-wide maps of the distribution synaptic inputs along these dendritic domains. In combination with electron microscopy, we aim to provide a nanoscale map of how excitation and inhibition emerges and is altered in CDKL5 knockout mice. This approach, currently used by the Burrone lab, has already uncovered important subcellular features in the distribution of synapses along basal and oblique dendrites in wild type hippocampal neurons [3, 4]. Determining region specific defects will enable us to focus on those areas for mechanistic studies.

Homeostatic synaptic plasticity is an important mechanism in the brain that serves to stabilize the activity of neurons and their networks [5]. Disrupted plasticity mechanisms may lead to epilepsy. To achieve this, changes mediated by gene transcription, translation and ion channel modifications/ transport have been proposed. Even though CDKL5 is regulated by neuronal activity [1], it is not known what role CDKL5 plays in homeostatic plasticity. In the second part of the project we propose to induce homeostatic forms of plasticity through chronic changes in neuronal or network activity to assess responses in CDKL5 knockouts, in dissociated neurons or organotypic slice cultures. We will complement the structural readouts described above with functional measures of synaptic and network activity that include electrophysiology and Ca+2 imaging. We predict that increases in network activity will bias the balance of synaptic inputs towards inhibition and/or expression of channels that may diminish neuronal excitability, whereas silencing network activity will do the opposite. Our detailed structural and functional measures of synaptic inputs will allow us to uncover any compensatory deficiencies that may arise in the CDKL5 mice.

Our ultimate aim is to determine how specific CDKL5 may contribute to changes in neuronal synapse distribution and neuronal homeostatic plasticity.

Candidate background
Background in biology or chemistry would be suitable. This project would suit candidates with a background in cell biology and an interest in neuroscience.

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2020 and will register for their PhD at Imperial College London.

Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) 13 NOVEMBER 2019. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.

Funding Notes

Successful applicants will be awarded a non-taxable annual stipend of £22,000 plus payment of university tuition fees. Students of all nationalities are eligible to apply.

References

1. Baltussen, L. L., Negraes, P. D., Silvestre, M., Claxton, S., Moeskops, M., Christodoulou, E., . . . Ultanir, S. K. (2018)

Chemical genetic identification of CDKL5 substrates reveals its role in neuronal microtubule dynamics.

EMBO Journal 37: e99763. PubMed abstract

2. Gross, G. G., Junge, J. A., Mora, R. J., Kwon, H.-B., Olson, C. A., Takahashi, T. T., . . . Arnold, D. B. (2013)

Recombinant probes for visualizing endogenous synaptic proteins in living neurons.

Neuron 78: 971-985. PubMed abstract

3. Grillo, F. W., Neves, G., Walker, A., Vizcay-Barrena, G., Fleck, R. A., Branco, T. and Burrone, J. (2018)

A distance-dependent distribution of presynaptic boutons tunes frequency-dependent dendritic integration.

Neuron 99: 275-282 e273. PubMed abstract

4. Walker, A. S., Burrone, J. and Meyer, M. P. (2013)

Functional imaging in the zebrafish retinotectal system using RGECO.

Front Neural Circuits 7: 34. PubMed abstract

5. Turrigiano, G. (2012)

Homeostatic synaptic plasticity: local and global mechanisms for stabilizing neuronal function.

Cold Spring Harbor Perspectives in Biology 4: a005736. PubMed abstract

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