Perinatal cannabinoids delay KCC2 expression and lead to neurodevelopmental abnormalities

大麻是使用最频繁的非法药物。母体围产期使用大麻与 对后代造成的一系列不利的神经发育后果。潜在的机制(S)仍然存在 不完全了解，但与受损的皮质神经元回路形成一致。一个协调一致的 转录和生理事件的程序控制着大脑皮层回路的组装。进化论 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开关是 对大脑皮层回路和相关行为的正常发展至关重要。该交换机主要是由 通过增加钾/氯共转运体KCC2的表达，将氯从细胞中排出。 在我们的初步实验中，我们发现服用合成大麻素或THC对 哺乳大鼠和小鼠出生后前10天DAMS抑制出生后PFC中KCC2的表达 10-15天，延长GABA兴奋PFC神经网络的时间。围产期接触也会受到损害 前额叶皮质突触可塑性和认知或社会行为在成年后代中的性别。 拟议的工作将跟进这些令人兴奋的初步数据，以确定近期和长期的 大麻素诱导的延迟KCC2表达的影响通过解决三个特定的目的。 目标1.确定大坝暴露于THC的早期分子、功能和行为后果 哺乳期男女子代的±CBD。这些实验将表征早期的 对PFC神经元回路的影响，确定了THC的机制(以及可能的拮抗作用 大麻二醇(CBD)延迟KCC2的表达，检测PFC的定位和水平 内源性大麻素系统和测量与生态相关的幼犬行为(超声波发声和 在母亲暴露于大麻类药物之后(母亲分离后的归巢)。 目的2.确定哺乳期接触THC±CBD的长期后果。这些 实验将确定哺乳期暴露THC±CBD是否对突触可塑性有持久影响 在青少年和成人中，对PFC内源性大麻素成分的水平或定位，对自然社会的影响 行为和认知功能。 目的3.采取战略，以改善在下列期间暴露于THC的长期有害后果 哺乳。这些实验将检验增强内源性大麻素信号(CB1阳性)的假设 变构调节剂或ECB降解抑制剂)将挽救行为和生理缺陷， 是PCE的结果。 这些实验的完成将揭示围产期接触THC对 神经元功能和行为，并为改善相关行为提供新的治疗策略 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.