Tubert, C. | Search bioRxiv

bioRxiv2024

Striatal cholinergic interneuron pause response requires Kv1 channels, is absent in dyskinetic mice, and is restored by dopamine D5 receptor inverse agonism

Striatal cholinergic interneurons (SCIN) exhibit pause responses conveying information about rewarding events, but the mechanisms underlying these pauses remain elusive. Thalamic inputs induce a pause mediated by intrinsic mechanisms and regulated by dopamine D2 receptors, though the underlying membrane currents are unknown. Moreover, the role of D5 receptors (D5R) has not been addressed so far. Here, we performed ex vivo studies showing that glutamate released by thalamic inputs in the dorsolateral striatum induces a burst in SCIN, followed by a pause mediated by the activation of a Kv1-dependent delayed rectifier current. Endogenous dopamine promotes this pause through D2R stimulation, while pharmacological stimulation of D5R suppresses it. Remarkably, this pause is absent in parkinsonian mice rendered dyskinetic by chronic L-DOPA treatment but can be reinstated acutely by the inverse D5R agonist clozapine. Blocking the Kv1 current eliminates the pause reinstated by the D5R inverse agonist. In contrast, the D2-type receptor agonists quinpirole and sumanirole failed to reinstate a pause in dyskinetic mice. In conclusion, stimulation of thalamic inputs induces an excitation followed by a pause in SCIN, which is lost in parkinsonian mice that have been rendered dyskinetic. This pause is mediated by delayed rectifier Kv1 channels, which are tonically blocked in dyskinetic mice by a mechanism depending on D5R ligand-independent activity. Targeting these alterations may have therapeutic value in Parkinsons disease. HighlightsO_LIIn brain slices, thalamostriatal input triggers a burst followed by a pause in SCIN. C_LIO_LIKv1, but not Kv7 or Kir2.2 channels, are necessary for the expression of this pause. C_LIO_LID2R stimulation promotes, and D5R stimulation inhibits this pause. C_LIO_LIThalamic-induced bursts are not followed by a pause in SCIN from dyskinetic mice. C_LIO_LID2R stimulation does not reinstate a pause in dyskinetic mice. C_LIO_LID5R inverse agonism restores a Kv1-dependent pause response in dyskinetic mice. C_LI

neuroscience↗

bioRxiv2023

Feed-forward metabotropic signaling by Cav1 Ca2+ channels supports pacemaking in pedunculopontine cholinergic neurons

Like a handful of other neuronal types in the brain, cholinergic neurons (CNs) in the pedunculopontine nucleus (PPN) are lost in the course of Parkinsons disease (PD). Why this is the case is unknown. One neuronal trait implicated in PD selective neuronal vulnerability is the engagement of feed-forward stimulation of mitochondrial oxidative phosphorylation (OXPHOS) to meet high bioenergetic demand, leading to sustained oxidant stress and ultimately degeneration. The extent to which this trait is shared by PPN CNs is unresolved. To address this question, a combination of molecular and physiological approaches were used. These studies revealed that PPN CNs are autonomous pacemakers with modest spike-associated cytosolic Ca2+ transients. These Ca2+ transients were attributable in part to the opening of high-threshold Cav1.2 Ca2+ channels, but not Cav1.3 channels. Nevertheless, Cav1.2 channel signaling through endoplasmic reticulum ryanodine receptors stimulated mitochondrial OXPHOS to help maintain cytosolic adenosine triphosphate (ATP) levels necessary for pacemaking. Inhibition of Cav1.2 channels led to recruitment of ATP-sensitive K+ channels and slowing of pacemaking. Cav1.2 channel-mediated stimulation of mitochondria increased oxidant stress. Thus, PPN CNs have a distinctive physiological phenotype that shares some, but not all, of the features of other neurons that are selectively vulnerable in PD.

neuroscience↗