Every second throughout life, cortical circuitry efficiently compresses and interprets huge volumes of incoming sensory information. This high fidelity sensory processing guides normal brain development and is essential for animals’ successful interaction with the environment. Low-level sensory perceptual disturbance is nearly ubiquitous in Autism Spectrum Disorder (ASD), but despite the potential to offer crucial insight into the abnormal development of higher brain function is poorly understood. Fragile X Syndrome (FXS) is the most common heritable cause of ASD. Previous studies in the Fmr1-KO mouse model of FXS report cell-intrinsic, synaptic and local connectivity abnormalities in the neuronal physiology of primary sensory cortices. This suggests that sensory perceptual dysfunction could emerge from interacting circuit-wide pathophysiology to impair neural adaptations that support high fidelity sensory information processing. However, there is little mechanistic consensus about how this might occur. To address this, in this thesis I use brain slice electrophysiology and computer modelling to provide a bottom-up description of how thalamocortical (TC) responses, the principal cortical input for ascending sensory information, are mis-interpreted in the somatosensory Layer 4 (L4) circuit in Fmr1-KOs at a crucial developmental transition to active sensory processing. Recruitment of intracortical L4 network activity could be atypically evoked by lower frequency thalamic stimulation in Fmr1-KO slices. Furthermore, profound alterations to single-cell and network response dynamics were observed, in particular loss of spike timing precision considered critical for sensory circuit performance. These network phenomena were supported by interacting single-cell and local circuitry pathophysiology, including hyperexcitable cortical neurons and temporally distorted feed forward and feedback inhibition. Together, these data demonstrate cortical hypersensitivity to TC inputs and abnormal recruitment of network activity in critical period Fmr1-KO somatosensory cortical circuits. The hyperresponsiveness of intracortical circuitry may underlie tactile hyperexcitability and distorted sensory perception in FXS patients. Interestingly, modelling suggests that many of the alterations of synaptic and neuronal function are compensatory, thus minimizing the impact of the genetic lesion. Thus, this study shows for the first time that circuit level dysfunction emerges in the Fmr1-KO mouse from an accumulation of effects at the synaptic and cellular level; however, it also highlights the challenge of understanding which of these changes are pathological and which are compensatory.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:699934 |
| Date | January 2014 |
| Creators | Domanski, Aleksander Peter Frederick |
| Contributors | Kind, Peter ; Wyllie, David |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/18017 |
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