Project Details - Deficits and rescue of neuronal population coding in the sensory cortex of mouse models of autism spectrum disorders
|Supervisor(s): Dr Nathalie Rochefort, Dr Matthias Hennig & Prof Peter Kind|
|Centre/Institution: Centre for Integrative Physiology, School of Biomedical Sciences|
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.
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.
2. Cortical plasticity induced by monocular deprivation is altered in ASD/ID models.
3. Pharmacological treatments that rescue behavioural ASD/ID phenotypes in mouse models will modify cortical population activity and plasticity.
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.
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