Shank3(∆C/+) mice exhibit altered transcriptomic response to swim stress

Shank3 is a postsynaptic protein that complexes with group 1 metabotropic, AMPA-, and NMDA-type glutamate receptors. Mutations of Shank3 are causal for Phelan-McDermid syndrome (PMS) and associated autism phenotypes. Individuals with PMS often exhibit sensitivity to novelty or stress that can result in behavioral deterioration. Here we use a Shank3 mouse model with face-validity to PMS [Shank(3∆C/+)] and perform a transcriptomic analysis of principal neurons from neocortex of mice subjected to brief swim stress. Analysis reveals overrepresented pathways related to synapses accompanied by elevated expression of the immediate early gene Homer1a. In normal brain Homer1a is dynamically expressed in association with motivated behavior and mediates an essential step in sleep-related homeostatic down-scaling of synaptic proteins. This is consistent with observations that synaptic Shank3 expression requires Homer cross-linking, which is interrupted by Homer1a. Accentuated Homer 1a expression in Shank3(∆C/+) results in marked reductions of Shank3 expression, changes in synapse composition and NMDA-dependent synaptic plasticity, and disruption of social motivation. Deletion of Homer1a partially mitigates stress-induced phenotypes in Shank3(∆C/+) mice. Homer 1a is required for developmental plasticity, learning and memory, yet its enhanced expression in Shank3(∆C/+) may underlie a vulnerability of PMS patients that highlights the challenge of clinical management. Pyramidal Neuron mRNA profiles of Shank3(+/+) and Shank3(∆C/+) mice on C57BL6 strain background with and without swim stress