Tepper James M, Lee Christian R
Center for Molecular and Behavioral Neuroscience, Rutgers University, 197 University Avenue, Newark, NJ 07102, USA.
Prog Brain Res. 2007;160:189-208. doi: 10.1016/S0079-6123(06)60011-3.
At least 70% of the afferents to substantia nigra dopaminergic neurons are GABAergic. The vast majority of these arise from the neostriatum, the external globus pallidus and the substantia nigra pars reticulata. Nigral dopaminergic neurons express both GABA(A) and GABA(B) receptors, and are inhibited by local application of GABA(A) or GABA(B) agonists in vivo and in vitro. However, in vivo, synaptic responses elicited by stimulation of neostriatal or pallidal afferents, or antidromic activation of nigral pars reticulata GABAergic projection neurons are mediated predominantly or exclusively by GABA(A) receptors. The clearest and most consistent role for the nigral GABA(B) receptor in vivo is as an inhibitory autoreceptor that presynaptically modulates GABA(A) synaptic responses that originate from all three principal GABAergic inputs. The firing pattern of dopaminergic neurons is also effectively modulated by GABAergic inputs in vivo. Local blockade of nigral GABA(A) receptors causes dopaminergic neurons to shift to a burst firing pattern regardless of the original firing pattern. This is accompanied by a modest increase in spontaneous firing rate. The GABAergic inputs from the axon collaterals of the pars reticulata projection neurons seem to be a particularly important source of a GABA(A) tone to the dopaminergic neurons, inhibition of which leads to burst firing. The globus pallidus exerts powerful control over the pars reticulata input, and through the latter, disynaptically over the dopaminergic neurons. Inhibition of pallidal output leads to a slight decrease in firing of the dopaminergic neurons due to disinhibition of the pars reticulata neurons whereas increased firing of pallidal neurons leads to burst firing in dopaminergic neurons that is associated with a modest increase in spontaneous firing rate and a significant increase in extracellular levels of dopamine in the neostriatum. The pallidal disynaptic disinhibitory control of the dopaminergic neurons dominates the monosynaptic inhibitory influence because of a differential sensitivity to GABA of the two nigral neuron types. Nigral GABAergic neurons are more sensitive to GABA(A)-mediated inhibition than dopaminergic neurons, in part due to a more hyperpolarized GABA(A) reversal potential. The more depolarized GABA(A) reversal potential in the dopaminergic neurons is due to the absence of KCC2, the chloride transporter responsible for setting up a hyperpolarizing Cl(-) gradient in most mature CNS neurons. The data reviewed in this chapter have made it increasingly clear that in addition to the effects that nigral GABAergic output neurons have on their target nuclei outside of the basal ganglia, local interactions between GABAergic projection neurons and dopaminergic neurons are crucially important to the functioning of the nigral dopaminergic neurons.
至少70%投射到黑质多巴胺能神经元的传入神经是γ-氨基丁酸（GABA）能的。其中绝大多数起源于新纹状体、外侧苍白球和黑质网状部。黑质多巴胺能神经元表达GABA（A）和GABA（B）受体，并且在体内和体外，局部应用GABA（A）或GABA（B）激动剂可抑制这些神经元。然而，在体内，刺激新纹状体或苍白球传入神经或黑质网状部GABA能投射神经元的逆向激活所引发的突触反应主要或完全由GABA（A）受体介导。黑质GABA（B）受体在体内最明确和最一致的作用是作为一种抑制性自身受体，其在突触前调节源自所有三种主要GABA能输入的GABA（A）突触反应。在体内，多巴胺能神经元的放电模式也受到GABA能输入的有效调节。局部阻断黑质GABA（A）受体会使多巴胺能神经元转变为爆发式放电模式，而不论其原始放电模式如何。这伴随着自发放电率的适度增加。黑质网状部投射神经元轴突侧支的GABA能输入似乎是多巴胺能神经元GABA（A）张力的一个特别重要的来源，抑制该来源会导致爆发式放电。苍白球对网状部的输入施加强大控制，并通过后者对多巴胺能神经元进行双突触控制。抑制苍白球输出会导致多巴胺能神经元放电略有减少，这是由于网状部神经元的去抑制，而苍白球神经元放电增加会导致多巴胺能神经元爆发式放电，这与自发放电率的适度增加以及新纹状体中多巴胺细胞外水平的显著增加有关。由于两种黑质神经元类型对GABA的敏感性不同，苍白球对多巴胺能神经元的双突触去抑制控制主导了单突触抑制作用。黑质GABA能神经元比多巴胺能神经元对GABA（A）介导的抑制更敏感，部分原因是GABA（A）反转电位更超极化。多巴胺能神经元中GABA（A）反转电位更去极化是由于缺乏钾-氯共转运体2（KCC2），该转运体负责在大多数成熟中枢神经系统神经元中建立超极化的Cl⁻梯度。本章综述的数据越来越清楚地表明，除了黑质GABA能输出神经元对基底神经节之外的靶核的作用外，GABA能投射神经元与多巴胺能神经元之间的局部相互作用对于黑质多巴胺能神经元的功能至关重要。
