Neuronal dysfunctions underlying Phelan-McDermid syndrome and theirs rescue by genetic and pharmacological modulation of mGlu5 signalling

Shank proteins are large scaffold proteins located at post synaptic density (PSD) of excitatory synapses and they have a crucial role in formation, maturation and function of synapses. It is known that haploinsufficiency of SHANK3 is the major cause of neurological symptoms associated with Phelan-McDermid Syndrome (PMS), which includes hypotonia, global developmental delay, language and speech delay, and autistic behaviour. Indeed, Shank3 is essential to mediate mGluR5 signalling by recruiting Homer1b/c, another scaffold protein, to the PSD. We previously demonstrate that mGluR5 signalling pathway was altered in absence of Shank3 and that the improvement of mGluR5 activity with a positive allosteric modulator (PAM), named CDPPB, ameliorated functional and behavioural defects observed in Shank3 ex11 - /- mice. These data suggest that alteration in mGluR5 signalling pathway might be involved in the pathogenesis of PMS. In this work we want better clarify which is the contribution to different brain areas (striatum, prefrontal cortex and hippocampus) to the neurological symptoms of PMS and test the ability of VU0409551, a novel PAM of mGlu5 receptors, to rescue behavioural and synaptic dysfunction in Shank3 ex11 -/- mice. We found that acute treatment with VU0409551 rescues repetitive and stereotyped behaviour, social impairments and memory defects found in Shank3 ex11 -/- mice. Moreover, by selectively knocking down Shank3 in striatum, prefrontal cortex or hippocampus we defined behavioural symptoms of PMS that are specifically related to the three different brain areas. Interestingly acute treatment with VU0409551 was also able to reverse these behavioural deficits. At the molecular levels our results showed a specific reduction of protein translation in cortex and striatum of Shank3 ex11 -/- mice that can be rescued by treatment with VU0409551. In summary, our results suggest that mGluR5 signalling is impaired in absence of Shank3 and that mGluR5 PAMs may represent a new pharmacologic approach for treating patients affected by PMS.