Whissell Paul D, Avramescu Sinziana, Wang Dian-Shi, Orser Beverley A
From the *Department of Psychology, and †Institute of Medical Science, University of Toronto, Toronto, Canada; ‡Department of Anesthesia, Sunnybrook Health Sciences Centre, Toronto, Canada; and Departments of §Anesthesia and ‖Physiology, University of Toronto, Toronto, Canada.
Anesth Analg. 2016 Nov;123(5):1247-1252. doi: 10.1213/ANE.0000000000001373.
Extrasynaptic γ-aminobutyric acid type A (GABAA) receptors that contain the δ subunit (δGABAA receptors) contribute to memory performance. Dysregulation of δGABAA receptor expression, which occurs in some neurological disorders, is associated with memory impairment. Mice lacking δGABAA receptors (Gabrd) exhibit deficits in their ability to distinguish between similar memories, a process which is referred to as pattern separation. The CA3 and dentate gyrus subfields of the hippocampus regulate pattern separation, raising the possibility that synaptic plasticity is impaired in these regions in Gabrd mice. Although long-term potentiation (LTP), the most widely studied form of synaptic plasticity, is normal in the dentate gyrus of Gabrd mice, LTP in the CA3 subfield has not been studied. Here, we tested the hypothesis that LTP is reduced in the CA3 subfield of Gabrd mice.
LTP of extracellular field postsynaptic potentials was studied in the mossy fiber (MF)-CA3 pathway using hippocampal slices from Gabrd and wild-type (WT) mice. We also examined paired pulse responses and input-output relationships at MF-CA3 synapses.
MF-CA3 LTP was reduced in Gabrd mice, as evidenced by decreased potentiation of field postsynaptic potentials (WT: 178.3% ± 16.1% versus Gabrd: 126.3% ± 6.9%; P = 0.0091). Thus, the deletion of δGABAA receptors is associated with impaired plasticity. Bicuculline (BIC), a GABAA receptor antagonist, reduced plasticity in WT but not in Gabrd mice (WT + BIC: 123.9% ± 7.6% versus Gabrd + BIC: 136.5% ± 7.0%). Paired pulse responses and input-output relationships did not differ between the genotypes (all Ps > 0.05).
Both genetic deletion and pharmacological blockade of δGABAA receptors impair MF-CA3 LTP, suggesting that δGABAA receptors are necessary for synaptic plasticity in the CA3 subfield. Drugs that enhance δGABAA receptor function may reverse deficits in synaptic plasticity in the CA3 subfield and improve pattern separation in neurological disorders.
含有δ亚基的突触外γ-氨基丁酸A型（GABAA）受体（δGABAA受体）有助于记忆表现。δGABAA受体表达失调发生在一些神经疾病中，与记忆障碍有关。缺乏δGABAA受体（Gabrd）的小鼠在区分相似记忆的能力上存在缺陷，这一过程被称为模式分离。海马体的CA3和齿状回子区域调节模式分离，这增加了Gabrd小鼠这些区域突触可塑性受损的可能性。虽然长期增强（LTP）是研究最广泛的突触可塑性形式，在Gabrd小鼠的齿状回中是正常的，但CA3子区域的LTP尚未被研究。在这里，我们测试了Gabrd小鼠CA3子区域LTP降低的假设。
使用来自Gabrd和野生型（WT）小鼠的海马切片，研究苔藓纤维（MF）-CA3通路中细胞外场突触后电位的LTP。我们还检查了MF-CA3突触处的双脉冲反应和输入-输出关系。
Gabrd小鼠的MF-CA3 LTP降低，场突触后电位增强减少证明了这一点（WT：178.3%±16.1%对Gabrd：126.3%±6.9%；P = 0.0091）。因此，δGABAA受体的缺失与可塑性受损有关。荷包牡丹碱（BIC），一种GABAA受体拮抗剂，降低了WT小鼠的可塑性，但对Gabrd小鼠没有影响（WT + BIC：123.9%±7.6%对Gabrd + BIC：136.5%±7.0%）。不同基因型之间的双脉冲反应和输入-输出关系没有差异（所有P>0.05）。
δGABAA受体的基因缺失和药理学阻断均损害MF-CA3 LTP，表明δGABAA受体是CA3子区域突触可塑性所必需的。增强δGABAA受体功能的药物可能会逆转CA3子区域突触可塑性的缺陷，并改善神经疾病中的模式分离。
