Chemogenetic regulation of the TARP-lipid interaction mimics LTP and reversibly modifies behavior

• Published in: Cell reports (Cambridge) Vol. 42; no. 8; p. 112826
• Main Authors: Park, Joongkyu, Berthoux, Coralie, Hoyos-Ramirez, Erika, Shan, Lili, Morimoto-Tomita, Megumi, Wang, Yixiang, Castillo, Pablo E., Tomita, Susumu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.08.2023; Elsevier
• Subjects: AMPA receptor; amygdala; auxiliary subunits; CaMKII; chemogenetics; CP: Cell biology; CP: Neuroscience; fear conditioning; lipid; phosphorylation; synaptic plasticity; synaptic transmission; AMPA receptor; amygdala; CaMKII; fear conditioning; CP: Cell biology; CP: Neuroscience; chemogenetics; auxiliary subunits; synaptic transmission; synaptic plasticity; lipid; phosphorylation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112826

Long-term potentiation (LTP), a well-characterized form of synaptic plasticity, is believed to underlie memory formation. Hebbian, postsynaptically expressed LTP requires TARPγ-8 phosphorylation for synaptic insertion of AMPA receptors (AMPARs). However, it is unknown whether TARP-mediated AMPAR insertion alone is sufficient to modify behavior. Here, we report the development of a chemogenetic tool, ExSYTE (Excitatory SYnaptic Transmission modulator by Engineered TARPγ-8), to mimic the cytoplasmic interaction of TARP with the plasma membrane in a doxycycline-dependent manner. We use this tool to examine the specific role of synaptic AMPAR potentiation in amygdala neurons that are activated by fear conditioning. Selective expression of active ExSYTE in these neurons potentiates AMPAR-mediated synaptic transmission in a doxycycline-dependent manner, occludes synaptically induced LTP, and mimics freezing triggered by cued fear conditioning. Thus, chemogenetic controlling of the TARP-membrane interaction is sufficient for LTP-like synaptic AMPAR insertion, which mimics fear conditioning. [Display omitted] •ExSYTE, a chemogenetic tool, can control protein-lipid electrostatic interactions•Dissociation of the TARP cytoplasmic domain from plasma membranes mimics AMPAR-LTP•A subthreshold conditioning induces c-Fos expression in the amygdala without freezing•ExSYTE expression in activated amygdala neurons reversibly controls freezing A chemogenetic tool, ExSYTE, controls the interaction of TARP with plasma membranes and potentiates AMPAR-mediated transmission, thereby mimicking synaptically induced LTP. Selective expression of ExSYTE in activated neurons modifies behavior in a chemogenetic manner.