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bioRxiv · 10.1101/2020.07.01.181925

Inhibitory ultrapotent chemogenetics activate dopamine D1 receptor-expressing medium spiny neurons

Gantz, S. C.·Ortiz, M. M.·Belilos, A. J.·Moussawi, K.
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Abstract

Ultrapotent chemogenetics, including the chloride-permeable inhibitory PSAM4-GlyR receptor, were recently proposed as a powerful strategy to selectively control neuronal activity in awake, behaving animals. We aimed to validate the inhibitory function of PSAM4-GlyR in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) in the ventral striatum. Activation of PSAM4-GlyR with the uPSEM792 ligand enhanced rather than suppressed the activity of D1-MSNs in vivo as indicated by increased c-fos expression in D1-MSNs. Whole-cell recordings in mouse brain slices showed that activation of PSAM4-GlyR did not inhibit firing of action potentials in D1-MSNs. Activation of PSAM4-GlyR depolarized D1-MSNs, attenuated GABAergic inhibition, and shifted the reversal potential of PSAM4-GlyR current to more depolarized potentials, perpetuating the depolarizing effect of receptor activation. The data show that inhibitory PSAM4-GlyR chemogenetics may actually activate certain cell types, and highlight the pitfalls of utilizing chloride conductances to inhibit neurons.

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Gantz, S. C., Ortiz, M. M., Belilos, A. J., Moussawi, K.. 2020-07-01. Inhibitory ultrapotent chemogenetics activate dopamine D1 receptor-expressing medium spiny neurons. https://doi.org/10.1101/2020.07.01.181925

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