Background & Aims
Autism spectrum disorder (ASD) is associated with altered tactile and pain experiences (Moore, 2015). However, the underlying mechanisms are poorly understood. De novo mutations in SYNGAP1 are one of the most common genetic causes of neurodevelopmental disorders linked to intellectual disability, epilepsy, and ASD (Satterstrom et al., 2020). SYNGAP1 haploinsufficiency has also been associated with somatosensory processing alterations in humans and in mice (Michaelson et al., 2018). Many ASD-associated genes are key components of activity-dependent processes, suggesting potential involvement in the postnatal maturation of spinal somatosensory circuits (Ebert and Greenberg, 2013; Beggs et al., 2002). A rat SYNGAP1 haploinsufficiency model provides a new tool to study somatosensory processing in neurodevelopmental disorders. Our aim is to investigate the impact of heterozygous loss of SYNGAP1 on touch and pain behavioural phenotype and underlying spinal processing.
Methods
Adult male and female Syngap+/- and wild-type (n=11/genotype) rats underwent tactile, noxious mechanical, and noxious thermal behavioural testing. Spinal cord (n=7/genotype) was immunostained for markers of tactile (VGLUT1) and nociceptive (IB4) fibres. Glabrous skin (n=7/genotype) was immunostained for markers of tactile end organs (S100/NF200/ColIV). Isolated dorsal roots were stimulated at 0.2Hz/1-500µA in compound action potential (CAP) recordings (n=8/genotype). A?-fibre refractory period was measured at 1Hz/20µA in 2 ms steps between 20ms-2ms interpulse intervals and C-fibre activity-dependent slowing (ADS) was assessed in response to x40 stimuli at 1Hz/250µA. Dorsal root-ventral root potential (DR-VRP) recordings (n=7/genotype) were performed by stimulating dorsal roots at 0.2Hz/2.5-300µA, while cumulative depolarisation was assessed in response to x20 stimuli at 2Hz/300µA.
Results
Syngap+/- rats show reduced tactile reactivity but unaltered reactivity to noxious stimuli. The gross spinal termination pattern of tactile and nociceptive afferents is unaltered. Glabrous hindpaw skin structure and the density of tactile corpuscles does not differ between genotypes. There are no differences in electrical properties of the A?, A?, and C-fibre primary afferent components in CAP recordings, including no difference in the A?-fibre refractory period and C-fibre ADS. Spinal reflex networks have an increased response threshold in DR-VRP recordings, but unaltered response magnitude and cumulative depolarisation at maximal response intensity.
Conclusions
Tactile reactivity is reduced but acute pain reactivity is unaltered in Syngap+/- rats. Electrophysiological evidence of an increased threshold of Syngap+/- spinal reflexes indicates a spinal functional deficit contributes to the tactile hypo-reactivity phenotype we have observed in Syngap+/- rats.
References
Beggs, S., Torsney, C., Drew, L. J. and Fitzgerald, M. (2002) ‘The postnatal reorganization of primary afferent input and dorsal horn cell receptive fields in the rat spinal cord is an activity-dependent process’, Eur J Neurosci, 16(7), pp. 1249-58.
Ebert, D. H. and Greenberg, M. E. (2013) ‘Activity-dependent neuronal signalling and autism spectrum disorder’, Nature, 493(7432), pp. 327-37.
Michaelson, S. D., Ozkan, E. D., Aceti, M., Maity, S., Llamosas, N., Weldon, M. et al. (2018) ‘SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits’, Nat Neurosci, 21(12), pp. 1-13.
Moore, D. J. (2015) ‘Acute pain experience in individuals with autism spectrum disorders: a review’, Autism, 19(4), pp. 387-99.
Satterstrom, F. K., Kosmicki, J. A., Wang, J., Breen, M. S., De Rubeis, S., An, J.-Y. et al. (2020) ‘Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism’, Cell, 180(3), pp. 568-584.e23.
Presenting Author
Ying Sze
Poster Authors
Katarzyna Mazur
Centre for Discovery Brain Sciences, University of Edinburgh
Lead Author
Ying Sze
University of Edinburgh
Lead Author
Lewis Scott
Centre for Discovery Brain Sciences, University of Edinburgh
Lead Author
Carole Torsney
Centre for Discovery Brain Sciences
Lead Author
Topics
- Pain in Special Populations: Intellectual, Developmental, and Functional Disability