Excitation of medium spiny neurons by ‘inhibitory’ ultrapotent chemogenetics via shifts in chloride reversal potential

Ultrapotent chemogenetics, including the chloride-permeable inhibitory PSAM 4 -GlyR receptor, were recently proposed as a powerful strategy to selectively control neuronal activity in awake, behaving animals. We aimed validate function of dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) ventral striatum. Activation with uPSEM 792 ligand enhanced rather than suppressed D1-MSNs vivo indicated by increased c-fos expression and vitro cell-attached recordings from mouse brain slices. Whole-cell showed that activation depolarized D1-MSNs, attenuated GABAergic inhibition, shifted reversal potential current more potentials, perpetuating depolarizing effect receptor activation. These data show ‘inhibitory’ chemogenetics may activate certain cell types highlight pitfalls utilizing chloride conductances inhibit neurons.