Shank2 expression identifies a subpopulation of glycinergic interneurons involved in nociception and altered in an autism mouse model
olde Heuvel, F.; Ouali-Alami, N.; Wilhelm, H.; Deshpande, D.; Khatamsaz, E.; Catanese, A.; Woelfle, S.; Schoen, M.; Jain, S.; Grabrucker, S.; Ludolph, A. C.; Verpelli, C.; Michaelis, J.; Boeckers, T.; Roselli, F.
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Patients suffering from Autism Spectrum Disorders (ASD) experience disturbed nociception in form of either hyposensitivity to pain or hypersensitivity and allodynia. We have determined that Shank2-KO mice, which recapitulate the genetic and behavioural disturbances of ASD, display increased sensitivity to formalin pain and thermal, but not mechanical allodynia. We demonstrate that high levels of Shank2 expression identifies a subpopulation of neurons in murine and human dorsal spinal cord, composed mainly by glycinergic interneurons and that loss of Shank2 causes the decrease in NMDAR in excitatory synapses on these inhibitory interneurons. In fact, in the subacute phase of the formalin test, glycinergic interneurons are strongly activated in WT mice but not in Shank2-KO mice. As consequence, nociception projection neurons in lamina I are activated in larger numbers in Shank2-KO mice. Our findings prove that Shank2 expression identifies a new subset of inhibitory interneurons involved in reducing the transmission of nociceptive stimuli and whose unchecked activation is associated with pain hypersensitivity. Thus, we provide evidence that dysfunction of spinal cord pain processing circuits may underlie the nociceptive phenotypes in ASD patients and mouse models.
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