Chronic adolescent exposure to ∆9-tetrahydrocannabinol decreases NMDA current and extrasynaptic plasmalemmal density of NMDA GluN1 subunits in the prelimbic cortex of adult male mice.
Chronic adolescent exposure to ∆9-tetrahydrocannabinol decreases NMDA current and extrasynaptic plasmalemmal density of NMDA GluN1 subunits in the prelimbic cortex of adult male mice.
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青少年长期接触α9-四氢大麻酚会降低成年雄性小鼠前边缘皮质中的NMDA电流和NMDA GluN1亚基的突触外质膜密度。
DOI：
10.1038/s41386-019-0466-9
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Wang,Gang
中科院分区：
文献类型：
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作者：
Pickel,VirginiaM;Bourie,Faye;Chan,June;Mackie,Ken;Lane,DianeA;Wang,Gang
青春期是一个脆弱的发育时期，长期接触大麻中主要的精神活性化合物 Delta-9-四氢大麻酚 (Δ9-THC)，可能会导致参与情绪处理的前额皮质 (PFC) 边缘连接功能失调。大麻素-1 受体 (CB1R) 在很大程度上介导 Δ9-THC 和内源性大麻素的中枢神经效应，调节前边缘前额皮质 (PL-PFC) 谷氨酸能突触的 NMDA 受体依赖性突触可塑性。因此，青春期期间 Δ9-THC 长期占据 CB1R 可能会竞争性降低成熟 PL-PFC 中 NMDA 受体的功能表达和活性。我们使用多学科方法在成年 C57BL/6J 雄性小鼠中检验这一假设，这些小鼠在青春期（出生后 29-43 天）接受媒介物或 Δ9-THC 剂量递增（2.5-10 mg/kg/ip）。与媒介物相比，接受 9-THC 的小鼠表现出超极化的静息膜电位、自发放电率降低、电流诱导放电阈值增加以及通过电流钳记录分析的深层 PL-PFC 神经元中对 NMDA 的去极化反应降低。仅在青春期接受 Δ9-THC 的成年小鼠 PL-PFC 中的电子显微镜免疫标记显示，(1) 各种大小的树突中必需的 GluN1-NMDA 亚基的突触外质膜密度显着降低，(2) 主要接受 CB1R 标记的抑制型突触的大树突中 GluN1 的分布从细胞质转移到质膜分布终端。根据这些结果和伴随的行为研究，我们得出结论，男性青少年使用的大麻产品中过量摄入 Δ9-THC 导致的社会功能障碍可能在很大程度上反映了通过内源性大麻素调节的 NMDA 受体进行通信的 PL-PFC 网络的电路缺陷。
Adolescence is a vulnerable period of development when limbic connection of the prefrontal cortex (PFC) involved in emotional processing may be rendered dysfunctional by chronic exposure to delta-9-tetrahydrocannabinol (∆9-THC), the major psychoactive compound in marijuana. Cannabinoid-1 receptors (CB1Rs) largely mediate the central neural effects of ∆9-THC and endocannabinoids that regulate NMDA receptor-dependent synaptic plasticity of glutamatergic synapses in the prelimbic prefrontal cortex (PL-PFC). Thus, chronic occupancy of CB1Rs by ∆9-THC during adolescence may competitively decrease the functional expression and activity of NMDA receptors in the mature PL-PFC. We used a multidisciplinary approach to test this hypothesis in adult C57BL/6J male mice that received vehicle or ∆9-THC in escalating doses (2.5–10 mg/kg/ip) through adolescence (postnatal day 29–43). In comparison with vehicle, the mice receiving ∆9-THC showed a hyperpolarized resting membrane potential, decreased spontaneous firing rate, increased current-induced firing threshold, and decreased depolarizing response to NMDA in deep-layer PL-PFC neurons analyzed by current-clamp recordings. Electron microscopic immunolabeling in the PL-PFC of adult mice that had received Δ9-THC only during adolescence showed a significant (1) decrease in the extrasynaptic plasmalemmal density of obligatory GluN1-NMDA subunits in dendrites of all sizes and (2) a shift from cytoplasmic to plasmalemmal distribution of GluN1 in large dendrites receiving mainly inhibitory-type synapses from CB1R-labeled terminals. From these results and concomitant behavioral studies, we conclude that social dysfunctions resulting from excessive intake of ∆9-THC in the increasingly available marijuana products used by male teens may largely reflect circuit defects in PL-PFC networks communicating through endocannabinoid-regulated NMDA receptors.