| Summary: | <p>Abstract</p> <p>Background</p> <p>SHANK3 is a protein in the core of the postsynaptic density (PSD) and has a critical role in recruiting many key functional elements to the PSD and to the synapse, including components of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA), metabotropic glutamate (mGlu) and <it>N</it>-methyl-D-aspartic acid (NMDA) glutamate receptors, as well as cytoskeletal elements. Loss of a functional copy of the <it>SHANK3 </it>gene leads to the neurobehavioral manifestations of 22q13 deletion syndrome and/or to autism spectrum disorders. The goal of this study was to examine the effects of haploinsufficiency of full-length <it>Shank3 </it>in mice, focusing on synaptic development, transmission and plasticity, as well as on social behaviors, as a model for understanding <it>SHANK3 </it>haploinsufficiency in humans.</p> <p>Methods</p> <p>We used mice with a targeted disruption of <it>Shank3 </it>in which exons coding for the ankyrin repeat domain were deleted and expression of full-length Shank3 was disrupted. We studied synaptic transmission and plasticity by multiple methods, including patch-clamp whole cell recording, two-photon time-lapse imaging and extracellular recordings of field excitatory postsynaptic potentials. We also studied the density of GluR1-immunoreactive puncta in the CA1 stratum radiatum and carried out assessments of social behaviors.</p> <p>Results</p> <p>In <it>Shank3 </it>heterozygous mice, there was reduced amplitude of miniature excitatory postsynaptic currents from hippocampal CA1 pyramidal neurons and the input-output (I/O) relationship at Schaffer collateral-CA1 synapses in acute hippocampal slices was significantly depressed; both of these findings indicate a reduction in basal neurotransmission. Studies with specific inhibitors demonstrated that the decrease in basal transmission reflected reduced AMPA receptor-mediated transmission. This was further supported by the observation of reduced numbers of GluR1-immunoreactive puncta in the stratum radiatum. Long-term potentiation (LTP), induced either with θ-burst pairing (TBP) or high-frequency stimulation, was impaired in <it>Shank3 </it>heterozygous mice, with no significant change in long-term depression (LTD). In concordance with the LTP results, persistent expansion of spines was observed in control mice after TBP-induced LTP; however, only transient spine expansion was observed in <it>Shank3 </it>heterozygous mice. Male <it>Shank3 </it>heterozygotes displayed less social sniffing and emitted fewer ultrasonic vocalizations during interactions with estrus female mice, as compared to wild-type littermate controls.</p> <p>Conclusions</p> <p>We documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions in <it>Shank3 </it>heterozygous mice. Our results are consistent with altered synaptic development and function in <it>Shank3 </it>haploinsufficiency, highlighting the importance of Shank3 in synaptic function and supporting a link between deficits in synapse function and neurodevelopmental disorders. The reduced glutamatergic transmission that we observed in the <it>Shank3 </it>heterozygous mice represents an interesting therapeutic target in <it>Shank3</it>-haploinsufficiency syndromes.</p>
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