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Abstract:
Manipulating the function of neurons and circuits that translate
electrical and chemical signals into behavior represents a major
challenges in neuroscience. In addition to optogenetic methods using
light-activatable channels, pharmacogenetic methods with ligand induced
modulation of cell signaling and excitability have been developed.
However, they are largely based on ectopic expression of exogenous or
chimera proteins. Now, we describe the remote and reversible expression
of a Kir2.1 type potassium channel using the chemogenetic technique of
small molecule induced protein stabilization. Based on shield1-mediated
shedding of a destabilizing domain fused to a protein of interest and
inhibition of protein degradation, this principle has been adopted for
biomedicine, but not in neuroscience so far. Here, we apply this
chemogenetic approach in brain research for the first time in order to
control a potassium channel in a remote and reversible manner. We could
show that shield1-mediated ectopic Kir2.1 stabilization induces neuronal
silencing in vitro and in vivo in the mouse brain. We also validated
this novel pharmacogenetic method in different neurobehavioral
paradigms. The DD-Kir2.1 may complement the existing portfolio of
pharmaco- and optogenetic techniques for specific neuron manipulation,
but it may also provide an example for future applications of this
principle in neuroscience research.
