Excitation of medium spiny neurons by 'inhibitory' ultrapotent chemogenetics via shifts in chloride reversal potential.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33822716.
- Also identified by DOI 10.7554/eLife.64241 and PMC identifier 8024007.
- Licence recorded as CC0.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Ultrapotent chemogenetics, including the chloride-permeable inhibitory PSAM<sup>4</sup>-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 PSAM<sup>4</sup>-GlyR in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) in the ventral striatum. Activation of PSAM<sup>4</sup>-GlyR with the uPSEM<sup>792</sup> ligand enhanced rather than suppressed the activity of D1-MSNs in vivo as indicated by increased c-fos expression in D1-MSNs and in vitro as indicated by cell-attached recordings from D1-MSNs in mouse brain slices. Whole-cell recordings showed that activation of PSAM<sup>4</sup>-GlyR depolarized D1-MSNs, attenuated GABAergic inhibition, and shifted the reversal potential of PSAM<sup>4</sup>-GlyR current to more depolarized potentials, perpetuating the depolarizing effect of receptor activation. These data show that 'inhibitory' PSAM<sup>4</sup>-GlyR chemogenetics may activate certain cell types and highlight the pitfalls of utilizing chloride conductances to inhibit neurons.
Medical subject headings
- Chlorides
- Neurons
- Receptors, Dopamine D1
- Receptors, Glycine
- Ventral Striatum
- alpha7 Nicotinic Acetylcholine Receptor