Pain processing in a mouse model of Phelan-McDermid Syndrome, an autism spectrum disorder

Abstract

Approximately 75% of patients with Phelan-McDermid Syndrome (PMS), an autism spectrum disorder, exhibit diminished responses to pain. Pain hyporesponsivity (PH) puts patients at risk for aggravated consequences from injuries and can conceal life-threatening painful conditions. The consequences of abnormal sensory responses, including PH, have a negative impact on the quality of life for autistic children and their caregivers. However, the neurologic basis for PH in PMS is unclear. PMS is caused by mutations or deletions in one copy of Shank3. The Shank family proteins (Shank 1-3) are postsynaptic scaffold proteins that regulate the function of glutamate receptors. We used mice with heterozygous (HET) C-terminal truncation of Shank3 to determine the impact of this mutation on pain processing. Shank3 immunoreactivity was present in anterior cingulate cortex (ACC) and lumbar spinal cord (LSC) dorsal horns. Baseline responses to noxious heat and innocuous touch were similar between wild-type (WT) and HET mice. After spared nerve injury (SNI), tactile response thresholds were significantly higher in HET than those in WT at post-SNI days 8, 13, and 20. Western blotting revealed significant SNI-induced upregulation of Shank3, mGluR1, and Homer1b/c in ACC of WT and HETs. In LSC, baseline expression levels of Shank3, NR2A, GKAP, and PSD95 were significantly lower in HET than in WT mice. SNI significantly reduced WT LSC expression of Shank3 and GKAP. Co-immunoprecipitation with an antibody to Shank3 revealed decreased association with scaffolding proteins after SNI in WT and HET mice. In conclusion, Shank3 mutation alters behavioral and biochemical responses to neuropathic pain. Differing patterns of SNI-induced synaptic protein expression between LSC and ACC suggest that Shank3 may serve region-specific roles. Abnormal synaptic function due to Shank3 mutations may play a role in PH in PMS patients.