Inhibition of cholinergic interneurons potentiates corticostriatal transmission in D1 receptor-expressing medium-sized spiny neurons and restores motor learning in parkinsonian condition

Abstract

SUMMARYStriatal cholinergic interneurons (CINs) respond to salient or reward prediction-related stimuli after conditioning with brief pauses in their activity, implicating them in learning and action selection. This pause is lost in animal models of Parkinson’s disease. How this signal regulates the functioning of the striatum remains an open question. To address this issue, we examined the impact of CIN firing inhibition on glutamatergic transmission between the cortex and the medium-sized spiny projection neurons expressing dopamine D1 receptors (D1 MSNs). Brief interruption of CIN activity had no effect in control condition whereas it increased glutamatergic responses in D1 MSNs after nigrostriatal dopamine denervation. This potentiation was dependent upon M4 muscarinic receptor and protein kinase A. Decreasing CIN firing by opto/chemogenetic strategies in vivo rescued long-term potentiation in some MSNs and alleviated motor learning deficits in parkinsonian mice. Taken together, our findings demonstrate that the control exerted by CINs on corticostriatal transmission and striatal-dependent motor-skill learning depends on the integrity of dopaminergic inputs.

Cholinergic interneurons mediate cocaine extinction in male mice through plasticity across medium spiny neuron subtypes

“…To this end, during extinction, we inhibited ChINs using the designer receptor exclusively activated by designer drug hM4D(G i ) (G i -DREADD) ( Armbruster et al, 2007 ). To confirm that G i -DREADD inhibition decrease ACh events in vivo ( Aitta-Aho et al, 2017 ; Laverne et al, 2021 ; Lewis et al, 2020 ), we co-injected a ChAT∷Cre mouse with an adeno-associated virus (AAV)5 virus-expressing Cre-dependent hM4D(G i )-mCherry and GACh3.0 ( Figure 4A ), and found that the frequency and amplitude of ACh events were decreased 30 min after clozapine N -oxide (CNO) injection ( Figures 4B and 4C ).…”