Pauses in Cholinergic Interneuron Activity Are Driven by Excitatory Input and Delayed Rectification, with Dopamine Modulation

Summary

Cholinergic interneurons (ChIs) of the striatum pause their firing in response to salient stimuli and conditioned stimuli after learning. Several different mechanisms for pause generation have been proposed, but a unifying basis has not previously emerged. Here, using in vivo and ex vivo recordings in rat and mouse brain and a computational model, we show that ChI pauses are driven by withdrawal of excitatory inputs to striatum and result from a delayed rectifier potassium current (I _Kr) in concert with local neuromodulation. The I _Kr is sensitive to K _v7.2/7.3 blocker XE-991 and enables ChIs to report changes in input, to pause on excitatory input recession, and to scale pauses with input strength, in keeping with pause acquisition during learning. We also show that although dopamine can hyperpolarize ChIs directly, its augmentation of pauses is best explained by strengthening excitatory inputs. These findings provide a basis to understand pause generation in striatal ChIs.

Video Abstract

Highlights

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  Withdrawal of excitatory input to striatum induces pauses in ChIs

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  Delayed rectification by a K _v7-mediated potassium current (I _Kr) underlies pauses

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  Synapse weighting rather than direct hyperpolarization by dopamine promotes pauses

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  ChIs are faster to respond to excitatory input than striatal projection neurons

Abstract

Zhang et al. reveal how synchronized pause responses in striatal cholinergic interneurons are driven, through the response of a delayed rectifier current to withdrawal of excitatory inputs, in conjunction with dopamine acting to potentiate the pause during learning.