Chudomel O, Hasson H, Bojar M, Moshé S L, Galanopoulou A S
Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy Bronx, Albert Einstein College of Medicine, 1410 Pelham Pkwy South, Kennedy Rm 306, Bronx, NY, 10461, USA,
Neurochem Res. 2015 Apr;40(4):747-57. doi: 10.1007/s11064-015-1523-3. Epub 2015 Feb 3.
Previous studies have shown that the pharmacologic effects of GABAergic drugs and the postsynaptic phasic GABAAergic inhibitory responses in the anterior part of the rat substantia nigra pars reticulata (SNRA) are age- and sex-specific. Here, we investigate whether there are age- and sex-related differences in the expression of the δ GABAA receptor (GABAAR) subunit and GABAAR mediated tonic currents. We have used δ-specific immunochemistry and whole cell patch clamp to study GABAAR mediated tonic currents in the SNRA of male and female postnatal day (PN) PN5-9, PN11-16, and PN25-32 rats. We observed age-related decline, but no sex-specific changes, in bicuculline (BIM) sensitive GABAAR tonic current density, which correlated with the decline in δ subunit in the SNRA between PN15 and 30. Furthermore, we show that the GABAAR tonic currents can be modified by muscimol (GABAAR agonist; partial GABACR agonist), THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c)pyridin-3-ol: α4β3δ GABAARs agonist and GABACR antagonist), and zolpidem (α1-subunit selective GABAAR agonist) in age- and sex-dependent manner specific for each drug. We propose that the emergence of the GABAAR-sensitive anticonvulsant effects of the rat SNRA during development may depend upon the developmental decline in tonic GABAergic inhibition of the activity of rat SNRA neurons, although other sex-specific factors are also involved.
先前的研究表明，γ-氨基丁酸（GABA）能药物的药理作用以及大鼠黑质网状部前部（SNRA）的突触后阶段性GABAA能抑制反应具有年龄和性别特异性。在此，我们研究δ GABAA受体（GABAAR）亚基的表达以及GABAAR介导的强直电流是否存在与年龄和性别相关的差异。我们使用δ特异性免疫化学和全细胞膜片钳技术，研究了出生后第（PN）5-9天、PN11-16天以及PN25-32天的雄性和雌性大鼠SNRA中GABAAR介导的强直电流。我们观察到，荷包牡丹碱（BIM）敏感的GABAAR强直电流密度随年龄下降，但无性别特异性变化，这与PN15至30天之间SNRA中δ亚基的下降相关。此外，我们表明，GABAAR强直电流可被蝇蕈醇（GABAAR激动剂；部分GABACR激动剂）、THIP（4,5,6,7-四氢异恶唑并[5,4-c]吡啶-3-醇：α4β3δ GABAARs激动剂和GABACR拮抗剂）以及唑吡坦（α1亚基选择性GABAAR激动剂）以每种药物特有的年龄和性别依赖性方式进行调节。我们提出，尽管还涉及其他性别特异性因素，但大鼠SNRA在发育过程中对GABAAR敏感的抗惊厥作用的出现可能取决于对大鼠SNRA神经元活动的强直性GABA能抑制作用的发育性下降。
