乙醯膽鹼及血清素對外側蒼白球至視丘下核群聚性突觸傳導的調控作用

Abstract

The basal ganglia are comprised of the striatum, the globus pallidus, the subthalamic nucleus, and the substantia nigra. They participate in a variety of functions including: voluntary motor control, procedural learning, eye movement, cognitive and emotional functions. Because basal ganglia dysfunctions often lead to a wide spectrum of motor deficits, they are generally considered to be motor structures. It is well known that the functions of the basal ganglia are markedly modulated by different neuromodulators, and disturbances of these modulations may be related to diseases such as Parkinson’s disease (PD). The external globus pallidus (GPe) and the subthalamic nucleus (STN) are classically viewed as part of the indirect pathway. They are reciprocally connected and serve as a putative generator of pathological semi-rhythmic burst firings in PD. The aim of this research is to investigate the effect of different neuromodulators on the GABAergic synaptic transmission from GPe to STN. We recorded evoked inhibitory postsynaptic currents (eIPSCs) from GPe to STN in C57BL/6 mouse brain slices using whole-cell voltage-clamp technique. We gave trains of stimuli (5 pulses in a train) at three different frequencies (8 Hz, 20 Hz, and 80 Hz), attempting to simulate the spontaneous firing rates of GPe neurons of rodents. We found that cholinergic agonist (carbachol) markedly reduced the P1 amplitude of GABAergic eIPSCs and showed a tendency to increase both P2/P1 and P5/P1 ratios. The inhibitory effect of carbachol could be mimicked by muscarinic but not nicotinic agonists. Moreover, the modulatory effect of carbachol on GABAergic eIPSCs persisted in the presence of nicotinic antagonist (mecamylamine). To clarify the muscarinic subtype(s) involved, we further examined the effect of M1 agonist (cevimeline) and M2 agonist (arecaidine). We found that cevimeline had no apparent effect on GPe-STN synaptic transmission, while arecaidine exhibited inhibitory actions on synaptic currents in a concentration-dependent manner. In addition, M2 antagonist (AQ-RA 741) totally abolished the effect of carbachol. We also examined whether the dopamine system modulated GPe-STN synaptic transmission. D1 agonist (A68930) did not affect either the amplitude or the P2/P1 and P5/P1 ratios of GPe-STN synaptic currents. On the contrary, D2 agonist (B-HT 920) slightly increased the amplitude of GABAergic eIPSCs but had inconsistent effects on P2/P1 and P5/P1 ratios. However, D2 antagonists (eticlopride and L-741,626) alone failed to affect GPe-STN synaptic transmission. On the other hand, norepinephrine slightly boosted the amplitude of eIPSCs but did not affect either the P2/P1 or the P5/P1 ratio. Serotonergic agonist (5-CT) significantly decreased the amplitude of eIPSCs at relatively high concentrations with a tendency to increase the P2/P1 and P5/P1 ratios. We conclude that acetylcholine and serotonin could modulate the GPe-STN synaptic transmission.