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Studies of excitatory and inhibitory balance in autism


About This PhD Project

Project Description

Project Code: 2020-SIDB-04

Brain circuits require the balance between excitatory and inhibitory synapses. Autism has been proposed to be a disorder that alters the “excitatory-inhibitory” (E-I) balance in brain circuits. However, it is unclear how the genetic causes and cell biological mechanisms of autism lead to changes in the E-I balance. One of the major limitations has been the ability to quantify excitatory and inhibitory synapses.

Another major hypothesis is that abnormal protein synthesis is a general cause of autism. The link between E-I balance and protein synthesis is poorly understood, in part because of the technical problems in measuring protein synthesis in specific synapses and brain circuits.

To overcome the limitation in studying both excitatory and inhibitory synapses and their protein turnover, we have engineered mice that label proteins in excitatory and inhibitory synapses (PSD95 and Gephyrin, respectively) with protein domains that encode Halo, CLIP or SNAP CLIP tags. These highly versatile protein tags covalently bind to small molecules ligands (administered by different routes in vivo or in vitro) that are coupled to dyes for diffraction-limited confocal microscopy and super-resolution imaging. This can be used to quantify the protein as well as measure protein turnover (using a pulse chase paradigm). We can therefore quantify excitatory and inhibitory synapses as well as measure the rate of turnover of their proteomes at single synapse resolution. After optimizing and establishing these methods, the student will ask how mouse models of autism alter E-I balance and protein turnover in excitatory and inhibitory synapses. We will also explore how neuronal activity and behavioural experience of mice regulates these processes and potentially examine gene-environment interactions by asking how behavioural experience in mice carrying mutations modifies the excitatory and inhibitory synapses.

The project will involve genome engineering in mice using CRISPR and potentially dCAS9 viral activation or inhibition of autism genes in mice carrying the tagged synaptic proteins. The mouse brain tissues will be examined using molecular imaging methods including our recently published synaptome mapping tools and new methods of measuring protein turnover in individual synapses. Other methods will include protein biochemistry of the genetically labelled proteins.

References

1 Gogolla, N. et al. Common circuit defect of excitatory-inhibitory balance in mouse models of autism. J Neurodev Disord 1, 172-181, doi:10.1007/s11689-009-9023-x (2009).

2 Nelson, S. B. & Valakh, V. Excitatory/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders. Neuron 87, 684-698, doi:10.1016/j.neuron.2015.07.033 (2015).

3 Kelleher, R. J., 3rd & Bear, M. F. The autistic neuron: troubled translation? Cell 135, 401-406, doi:10.1016/j.cell.2008.10.017 (2008).

4 Zhu, F. et al. Architecture of the Mouse Brain Synaptome. Neuron 99, 781-799 e710, doi:10.1016/j.neuron.2018.07.007 (2018).

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