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Sensory hypersensitivity in autism spectrum disorders: Disrupted postnatal wiring of tactile spinal circuits?


About This PhD Project

Project Description

Project Code: 2020-SIDB-12

Sensory hypersensitivity is a major feature of neurodevelopmental autism spectrum disorders and contributes to aberrant social and cognitive behaviours(1). Neonates normally display sensory hypersensitivity that gradually resolves during development as somatosensory circuitry refines and matures(2). A major contributor to this postnatal development is refinement of afferent spinal connections. In the adult there is segregation of afferent input in the dorsal/sensory spinal cord with high threshold nociceptive inputs targeting superficial laminae and low threshold tactile inputs targeting deep laminae. However, in neonates tactile inputs additionally target the ‘nociceptive’ superficial lamina but gradually withdraw over the first few postnatal weeks to target only deeper lamina in the adult. The normal postnatal withdrawal of these low threshold inputs from superficial laminae is an activity-dependent process(3). Animals in which this developmental activity-dependent process is disrupted retain tactile input to superficial lamina in the adult and accordingly display sensory hypersensitivity. Notably, genes mutated in autism spectrum disorders are key components of activity-dependent neuronal signalling(4). This project will therefore test whether disrupted postnatal wiring of tactile-spinal circuits contributes to sensory hypersensitivity in autism.

The study will comprise three main components. A) Behavioural sensory phenotyping of rat models of autism related genes (Syngap, Cdkl-5, Fmr1, Neuroligin-3) will identify those with tactile hypersensitivity in the adult. B) In parallel anatomical studies will determine the termination pattern of nociceptive and tactile afferents in the spinal dorsal horn and correlate with any observed sensory hypersensitivity. C) To determine whether anatomical observations of low threshold input are functional, calcium imaging and/or patch clamp electrophysiological recordings from superficial spinal neurons in ex vivo slices will be employed in tactile hypersensitivity models. In addition, cross breeding of the neurodevelopmental rat models with activity-marker transgenics (FosEGFP rats) will enable targeted recording from superficial spinal neurons that process tactile inputs in vivo.

References

1. L. L. Orefice et al., Peripheral Mechanosensory Neuron Dysfunction Underlies Tactile and Behavioral Deficits in Mouse Models of ASDs. Cell 166, 299-313 (2016).

2. M. Fitzgerald, The development of nociceptive circuits. Nat.Rev.Neurosci. 6, 507-520 (2005).

3. S. Beggs, C. Torsney, L. J. Drew, M. Fitzgerald, The postnatal reorganization of primary afferent input and dorsal horn cell receptive fields in the rat spinal cord is an activity-dependent process. The European journal of neuroscience 16, 1249-1258 (2002).

4. D. H. Ebert, M. E. Greenberg, Activity-dependent neuronal signalling and autism spectrum disorder. Nature 493, 327-337 (2013).

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