کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5549028 | 1556599 | 2017 | 14 صفحه PDF | دانلود رایگان |
- Cholinergic activation induces persistent increase in excitability of dorsolateral striatal MSNs.
- It is associated with negative shift of AP threshold, decrease in AHP amplitude and increase in EPSP-AP coupling.
- M1 mAChR antagonist VU0255035 prevents the persistent increase in MSN excitability.
- M1 PAM VU0453595 potentiates the persistent increase in MSN excitability.
- VU0453595 enhances performance of mice in cue-dependent water-based T-maze.
The dorsolateral striatum is critically involved in movement control and motor learning. Striatal function is regulated by a variety of neuromodulators including acetylcholine. Previous studies have shown that cholinergic activation excites striatal principal projection neurons, medium spiny neurons (MSNs), and this action is mediated by muscarinic acetylcholine subtype 1 receptors (M1) through modulating multiple potassium channels. In the present study, we used electrophysiology techniques in conjunction with optogenetic and pharmacological tools to determine the long-term effects of striatal cholinergic activation on MSN intrinsic excitability. A transient increase in acetylcholine release in the striatum by optogenetic stimulation resulted in a long-lasting increase in excitability of MSNs, which was associated with hyperpolarizing shift of action potential threshold and decrease in afterhyperpolarization (AHP) amplitude, leading to an increase in probability of EPSP-action potential coupling. The M1 selective antagonist VU0255035 prevented, while the M1 selective positive allosteric modulator (PAM) VU0453595 potentiated the cholinergic activation-induced persistent increase in MSN intrinsic excitability, suggesting that M1 receptors are critically involved in the induction of this long-lasting response. This M1 receptor-dependent long-lasting change in MSN intrinsic excitability could have significant impact on striatal processing and might provide a novel mechanism underlying cholinergic regulation of the striatum-dependent motor learning and cognitive function. Consistent with this, behavioral studies indicate that potentiation of M1 receptor signaling by VU0453595 enhanced performance of mice in cue-dependent water-based T-maze, a dorsolateral striatum-dependent learning task.
Journal: Neuropharmacology - Volume 118, 15 May 2017, Pages 209-222