Neurosteroid effects on GABAergic synaptic plasticity in hippocampus
Neurosteroid effects on GABAergic synaptic plasticity in hippocampus
复制标题
DOI：
10.1152/jn.00780.2002
复制
发表时间：
2003-04-01
影响因子：
2.5
通讯作者：
Smith, SS
中科院分区：
文献类型：
--
作者：
Hsu, FC;Waldeck, R;Smith, SS
我们之前报道过，短期（48-72小时）暴露于GABA调节类固醇3alpha- oh -5alpha-pregnan-20-one （3alpha,5alpha-THP）会增加成年大鼠海马中GABA(A)受体(GABAR) α 4亚基的表达。这种亚基组成的变化伴随着药理学的改变和与gaba门控制电流的锥体细胞的衰减时间常数（tau）加速相关的一般兴奋性的增加，这与我们报道的慢性长期服用类固醇后停药后的情况相似。由于GABAR可以定位于突触或突触外位点，我们验证了受体动力学变化是由突触GABAR介导的假设。为此，我们评估了在3alpha，5alpha/ β - thp （10 mg/kg, ip）处理48小时后，海马CA1锥体细胞记录的ttx抗性微型抑瘤性突触后电流（mIPSCs）的衰减动力学。激素治疗显著加速了GABAergic mIPSCs的快速衰减时间常数（tau(fast)）。这种作用可以通过反义寡核苷酸抑制α 4亚基的表达来阻止，这表明激素治疗在亚突触上增加了含有α 4的GABAR。来自3alpha，5beta- thp处理动物的药理学数据进一步支持了这一结论，表明在使用α -4选择性苯二氮卓类药物RO15-4513后，单个mIPSCs的taus呈双峰分布，并向较慢的值转移。由于40-50%的个体tau在使用非α - 4选择性苯二氮卓激动剂劳拉西泮（LZM）后也转移到较慢的值，我们认为含有α - 4亚基的GABAR突触数量与使用3α， 5α - thp 48小时后不含α - 4亚基的GABAR突触数量相当。加速电流衰减导致gabar介导的电荷转移减少，可能导致海马回路的兴奋性增加，这与我们之前证明的行为兴奋性增加一致。
We have previously reported that short-term (48-72 h) exposure to the GABA-modulatory steroid 3alpha-OH-5alpha-pregnan-20-one (3alpha,5alpha-THP) increases expression of the alpha4 subunit of the GABA(A) receptor (GABAR) in the hippocampus of adult rats. This change in subunit composition was accompanied by altered pharmacology and an increase in general excitability associated with acceleration of the decay time constant (tau) for GABA-gated current of pyramidal cells acutely isolated from CA1 hippocampus similar to what we have reported following withdrawal from the steroid after chronic long-term administration. Because GABAR can be localized to either synaptic or extrasynaptic sites, we tested the hypothesis that this change in receptor kinetics is mediated by synaptic GABAR. To this end, we evaluated the decay kinetics of TTX-resistant miniature inhibitory postsynaptic currents (mIPSCs) recorded from CA1 pyramidal cells in hippocampal slices following 48-h treatment with 3alpha,5alpha/beta-THP (10 mg/kg, ip). Hormone treatment produced a marked acceleration in the fast decay time constant (tau(fast)) of GABAergic mIPSCs. This effect was prevented by suppression of alpha4-subunit expression with antisense ( AS) oligonucleotide, suggesting that hormone treatment increases alpha4-containing GABAR subsynaptically. This conclusion was further supported by pharmacological data from 3alpha,5beta-THP-treated animals, demonstrating a bimodal distribution of taus for individual mIPSCs following bath application of the alpha4-selective benzodiazepine RO15-4513, with a shift to slower values. Because 40-50% of the individual taus were also shifted to slower values following bath application of the non-alpha4-selective benzodiazepine agonist lorazepam (LZM), we suggest that the number of GABAR synapses containing alpha4 subunits is equivalent to those that do not following 48-h administration of 3alpha,5alpha-THP. The decrease in GABAR-mediated charge transfer resulting from accelerated current decay may then result in increased excitability of the hippocampal circuitry, an effect consistent with the increased behavioral excitability we have previously demonstrated.