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

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...

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Bibliographic Details
Published in:	Neuron (Cambridge, Mass.) Mass.), 2018-06, Vol.98 (5), p.918-925.e3
Main Authors:	Zhang, Yan-Feng, Reynolds, John N.J., Cragg, Stephanie J.
Format:	Article
Language:	eng
Subjects:	Animals Anthracenes - pharmacology basal ganglia cholinergic interneuron Cholinergic Neurons - drug effects Cholinergic Neurons - metabolism Computational neuroscience Computer Simulation Corpus Striatum - cytology Corpus Striatum - drug effects Corpus Striatum - metabolism corticostriatal delayed rectification Dopamine Dopamine - metabolism excitatory input Interneurons Interneurons - drug effects Interneurons - metabolism KCNQ2 Potassium Channel - antagonists & inhibitors KCNQ3 Potassium Channel - antagonists & inhibitors Learning Mice Models, Neurological Neostriatum Neuromodulation Neurons nigrostriatal pause response Potassium Channel Blockers - pharmacology Potassium channels (voltage-gated) Rats Software striatum thalamostriatal
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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 (IKr) in concert with local neuromodulation. The IKr is sensitive to Kv7.2/7.3 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. [Display omitted] •Withdrawal of excitatory input to striatum induces pauses in ChIs•Delayed rectification by a Kv7-mediated potassium current (IKr) underlies pauses•Synapse weighting rather than direct hyperpolarization by dopamine promotes pauses•ChIs are faster to respond to excitatory input than striatal projection neurons 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.
ISSN:	0896-6273 1097-4199