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PhD Project - Characterisation of tactile and pain sensitivity in a CRISPR/Cas9 Grin2b rat model of autism

Vacancy Reference Number
2022-SIDB-TORSNEY
Closing Date
16 Jan 2022
Address
University of Edinburgh

Background:

Altered tactile and pain sensitivity is a major feature of neurodevelopmental autism spectrum disorders and is thought to contribute to aberrant social and cognitive behaviours (1). Tactile hyposensitivity and hypersensitivity have been reported in both patients and preclinical models. Similarly, pain sensitivity can be reduced or heightened. The spinal cord circuits that gate and filter tactile and pain sensory information from the body, before relay to the brain, undergo significant activity-dependent postnatal development (2). Tactile and pain sensory inputs initially intermingle but gradually segregate in an NMDAR dependent manner. The GluN2B subunit of the NMDAR is expressed in the dorsal horn throughout this developmental period.

Rationale & hypothesis:

Given that variants in the Grin2b gene that encodes the GluN2B subunit are associated with autism (3) this project will characterise a CRISPR/Cas9 Grin2B (heterozygous knockout) rat model of autism. It is predicted that there will be altered postnatal maturation of spinal sensory circuits that will manifest in altered tactile/pain phenotypes. This will be explored in both sexes because there are sex differences in spinal GluN2B spinal expression (4) and notably, there is increasing awareness that autism presentation may differ between the sexes.

Aims:

The study will comprise three main aims:

  1. Use a range of somatosensory behavioural testing to assess whether there is altered tactile or pain sensitivity in the Grin2b rat model
  2. Use immunostaining anatomical approaches to assess whether postnatal segregation of nociceptive and tactile inputs to the spinal cord is altered in the Grin2b rat model
  3. Use patch clamp electrophysiological recordings from ex vivo spinal slices to determine whether there is altered functional processing in tactile and pain spinal circuits in the Grin2b rat model

Training outcomes:

  • Behavioural somatosensory phenotyping
  • Immunostaining and confocal imaging/analysis
  • Electrophysiology (extracellular compound action potential, patch-clamp electrophysiology)
  • Ex vivo nerve/spinal cord preparations