Saalmann Yuri B, Morgan Ian G, Calford Mike B
Department of Optometry and Vision Sciences, University of Melbourne, Corner of Keppel and Cardigan Streets, Carlton, Victoria 3053, Australia.
J Neurophysiol. 2006 Dec;96(6):3064-73. doi: 10.1152/jn.00786.2006. Epub 2006 Sep 13.
Fast inhibitory neurotransmission in the brain is largely mediated by the gamma-aminobutyric acid-type A (GABA(A)) receptor. The 3alpha,5alpha-reduced neurosteroids (e.g., allopregnanolone) are the most potent endogenous modulators of the GABA(A) receptor. Although it is known that 3alpha,5alpha-reduced neurosteroid levels change during stress or depression and over the estrus cycle, a basic physiological role consistent with their pharmacological action remains elusive. We used the unique architecture of the auditory midbrain to reveal a role for 3alpha,5alpha-reduced neurosteroids in regulating inhibitory efficacy. After blocking the massive GABAergic projection from the dorsal nucleus of the lateral lemniscus (DNLL) to the contralateral central nucleus of the inferior colliculus (ICC) in anesthetized rats, a reactive increase in the efficacy of other inhibitory circuits in the ICC (separable because of the dominant ear that drives each circuit) was demonstrated with physiological measures-single-neuron activity and a neural-population-evoked response. This effect was prevented by blocking 3alpha,5alpha-reduced neurosteroid synthesis with a 5alpha-reductase inhibitor: finasteride. Immunohistochemistry confirmed that the DNLL blockade induced an increase in 3alpha,5alpha-reduced neurosteroids in the contralateral ICC. This study shows that when GABAergic inhibition is reduced, the brain compensates within minutes by locally increasing synthesis of neurosteroids, thereby balancing excitatory and inhibitory inputs in complex neural circuits.
大脑中的快速抑制性神经传递主要由γ-氨基丁酸A型（GABA(A)）受体介导。3α,5α-还原神经甾体（如别孕烯醇酮）是GABA(A)受体最有效的内源性调节剂。尽管已知3α,5α-还原神经甾体水平在应激或抑郁期间以及发情周期中会发生变化，但其与药理作用一致的基本生理作用仍不清楚。我们利用听觉中脑独特的结构揭示了3α,5α-还原神经甾体在调节抑制效能中的作用。在麻醉大鼠中阻断从外侧丘系背核（DNLL）到对侧下丘中央核（ICC）的大量GABA能投射后，通过生理测量——单神经元活动和神经群体诱发反应，证明了ICC中其他抑制性回路的效能有反应性增加（由于驱动每个回路的优势耳而可分离）。用5α-还原酶抑制剂非那雄胺阻断3α,5α-还原神经甾体合成可防止这种效应。免疫组织化学证实，DNLL阻断诱导对侧ICC中3α,5α-还原神经甾体增加。这项研究表明，当GABA能抑制减弱时，大脑会在数分钟内通过局部增加神经甾体合成来进行补偿，从而平衡复杂神经回路中的兴奋性和抑制性输入。
