Prenatal exposure to Δ9-tetrahydrocannabinol (THC), the most prominent active constituent of cannabis, alters neurodevelopmental plasticity with a long-term functional impact on adult offspring. Specifically, THC affects the development of pyramidal neurons and GABAergic interneurons via cannabinoid CB1 receptors (CB1R). However, the particular contribution of these two neuronal lineages to the behavioral alterations and functional deficits induced by THC is still unclear. Here, by using conditional CB1R knockout mice, we investigated the neurodevelopmental consequences of prenatal THC exposure in adulthood, as well as their potential sex differences. Adult mice that had been exposed to THC during embryonic development showed altered hippocampal oscillations, brain hyperexcitability, and spatial memory impairment. Remarkably, we found a clear sexual dimorphism in these effects, with males being selectively affected. At the neuronal level, we found a striking interneuronopathy of CCK-containing interneurons in the hippocampus, which was restricted to male progeny. This THC-induced CCK-interneuron reduction was not evident in mice lacking CB1R selectively in GABAergic interneurons, thus pointing to a cell-autonomous THC action. In vivo electrophysiological recordings of hippocampal LFPs revealed alterations in hippocampal oscillations confined to the stratum pyramidale of CA1 in male offspring. In addition, sharp-wave ripples, a major high-frequency oscillation crucial for learning and memory consolidation, were also altered, pointing to aberrant circuitries caused by persistent reduction of CCK+ basket cells. Taken together, these findings provide a mechanistic explanation for the long-term interneuronopathy responsible for the sex-dimorphic cognitive impairment induced by prenatal THC.

中文翻译：

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长期海马神经元病变导致产前THC暴露引起的性别-二型性空间记忆障碍。

产前暴露于大麻中最突出的活性成分Δ9-四氢大麻酚（THC），会改变神经发育可塑性，并对成年后代产生长期功能影响。具体而言，四氢大麻酚通过大麻素CB1受体（CB1R）影响锥体神经元和GABA能神经元的发育。然而，这两个神经元谱系对由THC引起的行为改变和功能缺陷的具体贡献仍不清楚。在这里，通过使用条件性CB1R敲除小鼠，我们调查了成年前产前四氢大麻酚暴露对神经发育的影响，以及它们潜在的性别差异。在胚胎发育过程中接触过四氢大麻酚的成年小鼠表现出海马振荡改变，脑过度兴奋和空间记忆障碍。值得注意的是 我们发现在这些影响中明显存在性二态性，其中男性受到选择性影响。在神经元水平上，我们在海马体中发现了一个惊人的含有CCK的中间神经元的中间神经元病变，它仅限于雄性子代。这种THC诱导的CCK-中间神经元减少在GABA能性中间神经中选择性缺乏CB1R的小鼠中不明显，因此表明细胞具有自主THC作用。海马LFP的体内电生理记录显示，雄性后代的CA1锥体层限制了海马振荡的变化。此外，尖波波动（对学习和记忆整合至关重要的主要高频振荡）也已改变，这表明CCK +篮状细胞持续减少所引起的异常电路。在一起