Deficits and rescue of neuronal population coding in the sensory cortex of mouse models of autism spectrum disorders

Background

The central aim of this project is to understand the effects of single gene mutations at the level of cortical networks activity in animal models of Autisitic Spectrum Disorders (ASDs) and Intellectual disabilities (ID). Cortical circuits are initially defined by genetic programmes, followed by neural plasticity initially driven by spontaneous and later on by evoked sensory activity. The investigation of monogenic ASD/ID animal models at the cellular level has revealed multiple alterations in neuronal properties, including changes in excitability, synaptic transmission and neural plasticity. Yet it remains largely unknown how such cellular changes affect the activity in neural circuits, and how this, in turn, leads to the diversity of phenotypes characterising ASD/ID. Moreover, recent work indicates that some of these changes are of secondary nature, and likely result from a developmental homeostatic compensation of primary defects. In this scenario, an initial defect leads to altered cellular and/or network activity, which, in turn, is compensated by cellular feedback processes. It is therefore possible that different primary causes, for instance defective plasticity in Fragile X Syndrome and SYNGAP haploinsufficiency, can lead to similar defects at the circuit level. This convergence may provide an opportunity for interventions targeting the resulting cellular and circuit dysfunction in adults.

Addressing this gap in knowledge requires a comprehensive understanding of the circuit-level impairments of ASD/ID in adults. Very few studies have so far investigated network activity in disease models beyond global features such as seizures, and currently no coherent picture exists. Here, we plan to use Fmr1-/y and Syngap+/- mice as two well established ASD/ID models to determine how these mutations affect the propagation of neural activity through cortical networks, focussing on sensory areas where inputs are readily controllable.

Aims

We will examine the following three hypotheses in Fmr-/y and Syngap+/- mice in this project:

1. Cortical ensemble activity is consistently altered in ASD/ID models, compared to wild type (WT) animals, and biased towards reduced representational capabilities. This is predicted to be observable both for spontaneous (in darkness) and evoked activity in different behavioural states (stationary or locomotion). At the same time, we expect single neuron properties to be comparable to that of wild type animals, consistent with a pathology primarily expressed at the network level.

2. Cortical plasticity induced by monocular deprivation is altered in ASD/ID models. Computational modelling will be employed to investigate the extent to which this is a direct consequence of defective molecular synaptic and homeostatic plasticity pathways, and how altered network dynamics contribute to these differences.

3. Pharmacological treatments that rescue behavioural ASD/ID phenotypes in mouse models will modify cortical population activity and plasticity. Specifically, we expect that behavioural rescue restores cortical dynamics towards a regime comparable to that found in wild type animals.

To uncover the relevant circuit defects in ASD/ID models, we will use 2-photon calcium imaging of more than one thousand neurons simultaneously in the primary visual and parietal cortex, and employ computational data analysis and modelling. Genetically labelling of different interneuron types will enable a detailed dissection of the circuit pathology. We will investigate changes in experience-dependent plasticity at the circuit level, which has so far not been attempted, and evaluate the circuit-wide effects of pharmacological rescue in adults. Together, these complementary approaches will (i) help relate cellular and systems level pathologies in ASD/ID, (ii) explore avenues for treatment and interventions, and (iii) provide novel computational tools for analysis and interpretation of large neural population recordings.

Training Outcomes

In vivo imaging in awake behaving mice: training in 2-photon calcium imaging
Data Management: managing and analyzing big imaging data (100s GB)
Bioinformatics, Statistics and computational methods: model-based analysis of the data
Research Ethics, animal research regulations
Presentation of data, written and orally

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location:

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note you must apply to one of the projects and you are encouraged to contact the primary supervisor prior to making your application. Additional information on the application process if available from the link above.

For more information about Precision Medicine visit:

http://www.ed.ac.uk/usher/precision-medicine