Restoring the Function of Thalamocortical Circuit Through Correcting Thalamic Kv3.2 Channelopathy Normalizes Fear Extinction Impairments in a PTSD Mouse Model

Impaired extinction of fear memory is one of the most common symptoms in post-traumatic stress disorder (PTSD), with limited therapeutic strategies due to the poor understanding of its underlying neural substrates. In this study, functional screening is performed and identified hyperactivity in the mediodorsal thalamic nucleus (MD) during fear extinction. Furthermore, the encoding patterns of the hyperactivated MD is investigated during persistent fear responses using multiple machine learning algorithms. The anterior cingulate cortex (ACC) is also identified as a functional downstream region of the MD that mediates the extinction of fear memory. The thalamocortical circuit is comprehensively analyzed and found that the MD-ACC parvalbumin interneurons circuit is preferentially enhanced in PTSD mice, disrupting the local excitatory and inhibitory balance. It is found that decreased phosphorylation of the Kv3.2 channel contributed to the hyperactivated MD, primarily to the malfunctioning thalamocortical circuit. Using a lipid nanoparticle-based RNA therapy strategy, channelopathy is corrected via a methoxylated siRNA targeting the protein phosphatase 6 catalytic subunit and restored fear memory extinction in PTSD mice. These findings highlight the function of the thalamocortical circuit in PTSD-related impaired extinction of fear memory and provide therapeutic insights into Kv3.2-targeted RNA therapy for PTSD. This study links the overactive mediodorsal thalamic nucleus (MD) in PTSD mice to disrupted fear memory extinction via altered function of the thalamocortical circuit. A lipid nanoparticle RNA therapy targeting thalamic Kv3.2 channel phosphorylation is shown to correct these behavioral abnormalities in PTSD mice, providing a novel therapeutic strategy for PTSD.image