Understanding Autism Pathology: Insights from Genetic Mouse Model Manipulation of KCTD13 and SHANK3
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Copy number variations (CNVs) contribute to the etiology of Autism Spectrum Disorders (ASDs). Deletions/duplications in human chromosomal region 16p11.2 are frequently associated with ASD and other neurodevelopmental disorders. Specific genes within this region may be important for determining autism risk, though none has been individually linked to ASD. To understand how single 16p11.2 genes contribute to CNV deletion pathology, we delete a candidate among the 16p11.2 genes, Kctd13, in mice to examine its function in mammalian brain. We report that our Kctd13 deletion mouse model results in decreased synaptic transmission (input/output curves and mEPSC and mIPSC frequency) in area CA1 of the hippocampus with normal paired-pulse ratio, normal mEPSC/IPSC amplitude, and no change in another correlate of presynaptic release probability, suggesting a decrease in the number of functional synapses. Consistent with these results, reduced synaptic transmission correlates with increased levels of RhoA, the KCTD13/CUL3 ubiquitin ligase substrate, and is reversed by RhoA inhibition, confirming increased RhoA as one important molecular mechanism. These changes correlate with a decrease in total dendritic length and spine density in area CA1 of the hippocampus, confirming the decrease in synapse number. This genetic mouse model also displays increased locomotor activity, a robust behavioral phenotype in 16p11.2 deletion mouse models. These results suggest that KCTD13 regulates neuronal morphology and synapse number and likely does so via alteration of RhoA signaling pathways. Together, these data implicate Kctd13 in regulation of neuronal function relevant to neuropsychiatric disorders and reveal a potential role for RhoA as a future preclinical therapeutic target with potential to benefit patients containing KCTD13 deletions. SHANK3 (also known as PROSAP2) functions as a postsynaptic scaffolding protein at excitatory synapses. Mutations and deletions within SHANK3 are known to cause idiopathic autism, Phelan-McDermid (aka 22q13 microdeletion) syndrome, and other neuropsychiatric disorders. We create a novel mouse model of human autism caused by the insertion of a single guanine nucleotide into exon 21 (Shank3G). The resulting frameshift causes a premature STOP codon and loss of major higher molecular weight SHANK3 isoforms at the synapse. At the cellular level, Shank3G/G mice exhibit impaired hippocampal excitatory transmission and plasticity as well as changes in baseline NMDA receptor-mediated synaptic responses. Changes in NMDA receptor function correlate with decreased phosphorylation of the GluN2BR Tyr 1472 site in the Shank3G/G mice. These results identify clear alterations in synaptic function and in the biochemistry of NMDA receptors in a novel, genetically accurate mouse model of autism mimicking an autism-associated insertion mutation. These findings reveal a potential role for NMDA receptors as a preclinical therapeutic target for patients with SHANK3 mutations.
Nerve Tissue Proteins