Perinatal cannabinoids delay KCC2 expression and lead to neurodevelopmental abnormalities

大麻是使用最频繁的非法药物。产妇围产期使用大麻与 对后代的神经发育造成一系列不良后果。基本机制仍然存在 不完全理解，但与受损的皮层神经元回路形成一致。协调 转录和生理事件的程序控制着皮层回路的组装。进化 γ-氨基丁酸（GABA）从兴奋性神经递质到抑制性神经递质的保守转换， 对大脑皮层回路和相关行为的正常发育至关重要。开关主要由 通过增加钾/氯协同转运蛋白KCC 2的表达，KCC 2将氯从细胞中排出。 在我们的初步实验中，我们已经发现，给予合成大麻素或THC， 哺乳期大鼠和小鼠母鼠出生后前10天抑制出生后PFC中KCC 2的表达 第10-15天，延长GABA兴奋PFC网络的时间。围产期暴露也受损 前额叶皮层突触可塑性和认知或社会行为的成年后代的性别。 拟议的工作将跟进这些令人兴奋的初步数据，以确定直接和长期的 大麻素诱导的延迟KCC 2表达的影响，通过解决三个具体目标。 目标1。确定大坝暴露于THC的早期分子，功能和行为后果 ±哺乳期间两种性别后代的CBD。这些实验将描述早期 对PFC中神经元回路的影响，决定了THC的机制（以及可能的拮抗作用）。 大麻二酚（CBD））延迟KCC 2表达，检查PFC成分的定位和水平 内源性大麻素系统和测量生态相关的小狗行为（超声波发声和 母亲分离后归巢）。 目标二。确定哺乳期间THC ± CBD暴露的长期后果。这些 实验将确定哺乳期间THC ± CBD暴露是否对突触可塑性具有持久影响 在青少年和成人中，PFC内源性大麻素成分水平或定位，自然社会 行为和认知功能。 目标3：改善THC暴露的长期有害后果的策略 哺乳期这些实验将检验增强内源性大麻素信号传导（CB 1阳性） eCB降解的别构调节剂或抑制剂）将挽救 是PCE的后果。 这些实验的完成将揭示围产期THC暴露对新生儿的影响的基础。 神经元功能和行为，并提供新的治疗策略来改善相关的行为 赤字

Cannabis is the most frequently used illicit drug. Maternal perinatal cannabis use has been associated with a range of adverse neurodevelopmental consequences in the offspring. The underlying mechanism(s) remain incompletely understood, but are consistent with impaired cortical neuronal circuit formation. A coordinated program of transcriptional and physiological events governs the assembly of cortical circuits. The evolutionary conserved switch of gamma amino butyric acid (GABA) from an excitatory to an inhibitory neurotransmitter is crucial to the normal development of cortical circuits and associated behaviors. The switch is primarily driven by increased expression of a potassium/chloride co-transporter, KCC2, which extrudes chloride from the cell. In our preliminary experiments, we have found that administration of a synthetic cannabinoid or THC for the first 10 days after birth to lactating rat and mice dams suppresses KCC2 expression in the PFC at postnatal days 10-15, prolonging the time during which GABA excites PFC networks. Perinatal exposure also impaired prefrontal cortex synaptic plasticity and cognitive or social behaviors in the adult progeny of both sexes. The proposed work will follow up these exciting preliminary data to determine the immediate and long-lasting effects of the cannabinoid-induced delay in KCC2 expression by addressing three specific aims. Aim 1. Identify the early molecular, functional and behavioral consequences of exposing dams to THC ± CBD during lactation on the progeny of both sexes. These experiments will characterize the early consequences on neuronal circuits in the PFC, determine THC's mechanism (and possible antagonism by cannabidiol (CBD)) to delay KCC2 expression, examine the localization and levels of components of the PFC endocannabinoid system and measure ecologically-relevant pup behaviors (ultrasonic vocalizations and homing following maternal separation) after maternal exposure to cannabinoids. Aim 2. Determine the long-term consequences of THC ± CBD exposure during lactation. These experiments will determine if THC ± CBD exposure during lactation has enduring effects on synaptic plasticity in adolescent and adult, on levels or localization of PFC endocannabinoid components, on naturalistic social behaviors, and cognitive function. Aim 3. Strategies to ameliorate the long-term deleterious consequences of THC exposure during lactation. These experiments will test the hypothesis that enhancing endocannabinoid signaling (CB1 positive allosteric modulators or inhibitors of eCB degradation) will rescue the behavioral and physiological deficits that are a consequence of PCE. Completion of these experiments will reveal the underpinnings of the impact of perinatal THC exposure on neuronal functions and behavior and provide new therapeutic strategies to ameliorate associated behavioral deficits.