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Loss of KCTD13 Decreases Hippocampal Synaptic Transmission Via the Small Gtpase RhoA
Objectives: In an effort to understand how loss of Kctd13 might contribute to 16p11.2 deletion pathology, we created a Kctd13 deletion mouse.
Methods: Kctd13 effects on synaptic transmission were determined using extracellular and intracellular recordings of neurons in area CA1 of hippocampus from acute slices. CA1 neuronal morphology and spine density/morphology were analyzed using Golgi-Cox staining. Hippocampal lysate was tested biochemically for alterations in total and active RhoA protein levels via western blots and G-LISA RhoA Activation Assay (Cytoskeleton) respectively. Incubation of acute slice in Rho inhibitors occurred for 3.5 hours followed by extracellular and intracellular recordings of neurons in area CA1 of hippocampus.
Results: We have specifically deleted Kctd13 in mice and demonstrated reduced synaptic transmission correlated with decreased dendritic complexity and spine density in area CA1 the hippocampus. These alterations in synaptic transmission also correlate with increased levels of the KCTD13/CUL3 ubiquitin ligase substrate RhoA. Further, these synaptic phonotypes are reversed by selective RhoA inhibition in situ, confirming increased RhoA as the mechanism underlying reduced synaptic transmission.
Conclusions: These findings implicate Kctd13 in neuronal alterations that may contribute to neuropsychiatric disorders. These data implicate a potential role for RhoA as therapeutic target in disorders associated with deletion of KCTD13 including 16p11.2 deletion.