Diaz Marvin R, Vollmer Cyndel C, Zamudio-Bulcock Paula A, Vollmer William, Blomquist Samantha L, Morton Russell A, Everett Julie C, Zurek Agnieszka A, Yu Jieying, Orser Beverley A, Valenzuela C Fernando
Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Neuropharmacology. 2014 Apr;79:262-74. doi: 10.1016/j.neuropharm.2013.11.020. Epub 2013 Dec 4.
Exposure to ethanol (EtOH) during fetal development can lead to long-lasting alterations, including deficits in fine motor skills and motor learning. Studies suggest that these are, in part, a consequence of cerebellar damage. Cerebellar granule neurons (CGNs) are the gateway of information into the cerebellar cortex. Functionally, CGNs are heavily regulated by phasic and tonic GABAergic inhibition from Golgi cell interneurons; however, the effect of EtOH exposure on the development of GABAergic transmission in immature CGNs has not been investigated. To model EtOH exposure during the 3rd trimester-equivalent of human pregnancy, neonatal pups were exposed intermittently to high levels of vaporized EtOH from postnatal day (P) 2 to P12. This exposure gradually increased pup serum EtOH concentrations (SECs) to ∼60 mM (∼0.28 g/dl) during the 4 h of exposure. EtOH levels gradually decreased to baseline 8 h after the end of exposure. Surprisingly, basal tonic and phasic GABAergic currents in CGNs were not significantly affected by postnatal alcohol exposure (PAE). However, PAE increased δ subunit expression at P28 as detected by immunohistochemical and western blot analyses. Also, electrophysiological studies with an agonist that is highly selective for δ-containing GABA(A) receptors, 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol (THIP), showed an increase in THIP-induced tonic current. Behavioral studies of PAE rats did not reveal any deficits in motor coordination, except for a delay in the acquisition of the mid-air righting reflex that was apparent at P15 to P18. These findings demonstrate that repeated intermittent exposure to high levels of EtOH during the equivalent of the last trimester of human pregnancy has significant but relatively subtle effects on motor coordination and GABAergic transmission in CGNs in rats.
胎儿发育期间暴露于乙醇（EtOH）会导致长期改变，包括精细运动技能和运动学习方面的缺陷。研究表明，这些改变部分是小脑损伤的结果。小脑颗粒神经元（CGNs）是信息进入小脑皮质的门户。在功能上，CGNs受到来自高尔基细胞中间神经元的阶段性和紧张性GABA能抑制的严格调控；然而，乙醇暴露对未成熟CGNs中GABA能传递发育的影响尚未得到研究。为了模拟人类妊娠第三个月等效期的乙醇暴露情况，新生幼鼠从出生后第（P）2天至P12天间歇性暴露于高浓度的汽化乙醇中。在暴露的4小时内，这种暴露使幼鼠血清乙醇浓度（SECs）逐渐升高至约60 mM（约0.28 g/dl）。暴露结束后8小时，乙醇水平逐渐降至基线。令人惊讶的是，CGNs中的基础紧张性和阶段性GABA能电流并未受到出生后乙醇暴露（PAE）的显著影响。然而，通过免疫组织化学和蛋白质印迹分析检测到，PAE会增加P28时δ亚基的表达。此外，使用对含δ的GABA(A)受体具有高度选择性的激动剂4,5,6,7-四氢异恶唑并[4,5-c]吡啶-3-醇（THIP）进行的电生理研究表明，THIP诱导的紧张性电流增加。PAE大鼠的行为研究未发现运动协调方面有任何缺陷，只是在P15至P18时出现了空中翻正反射习得延迟。这些发现表明，在相当于人类妊娠最后三个月的时期内，反复间歇性暴露于高浓度乙醇对大鼠CGNs中的运动协调和GABA能传递有显著但相对细微的影响。
