Shank3 Exons 14–16 Deletion in Glutamatergic Neurons Leads to Social and Repetitive Behavioral Deficits Associated With Increased Cortical Layer 2/3 Neuronal Excitability

Abstract

Shank3, an abundant excitatory postsynaptic scaffolding protein, has been associated with multiple brain disorders, including autism spectrum disorders (ASD) and Phelan-McDermid syndrome (PMS). However, how cell type-specific <i>Shank3</i> deletion affects disease-related neuronal and brain functions remains largely unclear. Here, we investigated the impacts of <i>Shank3</i> deletion in glutamatergic neurons on synaptic and behavioral phenotypes in mice and compared results with those previously obtained from mice with global <i>Shank3</i> mutation and GABAergic neuron-specific <i>Shank3</i> mutation. Neuronal excitability was abnormally increased in layer 2/3 pyramidal neurons in the medial prefrontal cortex (mPFC) in mice with a glutamatergic <i>Shank3</i> deletion, similar to results obtained in mice with a global <i>Shank3</i> deletion. In addition, excitatory synaptic transmission was abnormally increased in layer 2/3 neurons in mice with a global, but not a glutamatergic, <i>Shank3</i> deletion, suggesting that Shank3 in glutamatergic neurons are important for the increased neuronal excitability, but not for the increased excitatory synaptic transmission. Neither excitatory nor inhibitory synaptic transmission was altered in the dorsal striatum of <i>Shank3</i>-deficient glutamatergic neurons, a finding that contrasts with the decreased excitatory synaptic transmission in global and <i>Shank3</i>-deficient GABAergic neurons. Behaviorally, glutamatergic <i>Shank3</i>-deficient mice displayed abnormally increased direct social interaction and repetitive self-grooming, similar to global and GABAergic <i>Shank3</i>-deficient mice. These results suggest that glutamatergic and GABAergic <i>Shank3</i> deletions lead to distinct synaptic and neuronal changes in cortical layer 2/3 and dorsal striatal neurons, but cause similar social and repetitive behavioral abnormalities likely through distinct mechanisms.