CB1 Receptor Action on the Developing Hippocampus

描述（由申请人提供）： 大麻（cannabis）使用的几个不利影响是公认的，包括对中枢神经系统的影响。 神经系统功能大麻对神经功能最显著的影响之一是对记忆的有害影响，这可能与海马体的损伤有关。 在大脑中，大麻素的作用是由CB 1受体（CB 1 R）转导的。CB 1 R在发育过程中高度表达，与Gi/Go偶联，抑制神经递质释放，并使神经元过度兴奋。虽然关于大麻和CB 1 R在成熟神经系统中的作用有相当多的信息，但对发育中的大脑的影响知之甚少。 越来越多的证据表明，在大脑生长的关键时期抑制神经元的活动将引发神经元凋亡。这表明发育中的大脑也对CB 1 R激活的影响敏感，我们观察到急性大麻素暴露诱导发育中的凋亡，但不诱导成熟的海马。 基于这些观察，我们提出了以下假设：（1）发育中的海马对CB 1 R激活的影响特别敏感。(2)大麻素在早期发育过程中的毒性是由于抑制神经元活动。 为了验证这些假设，我们将使用当代神经科学方法和CB 1 R敲除小鼠进行体内和体外研究。我们预计，这些研究将对大麻素作用对发育中大脑的潜在影响产生新的见解。

DESCRIPTION (provided by applicant): Several adverse effects of marijuana (cannabis) use are recognized including those on central nervous system function. Among the most prominent effects of cannabis on neural function are deleterious influences on memory, which may be related to damage to the hippocampus. In the brain, the effects of cannabinoids are transduced by the CB1 receptor (CB1R). CB1Rs are highly expressed during development, couple with Gi/Go, inhibit neurotransmitter release, and hyperpolarize neurons. Whereas a considerable amount of information is known about cannabis and CB1R action in the mature nervous system, relatively little is known about effects on the developing brain. Increasing evidence suggests that suppression of neuronal activity during critical periods of brain growth will trigger neuronal apoptosis. Suggesting that the developing brain is also sensitive to effects of CB1R activation, we observe that acute cannabinoid exposure induces apoptosis in the developing, but not mature hippocampus. Based on these observations, we propose to test the hypotheses that (1) the developing hippocampus is especially sensitive to the effects of CB1R activation. (2) Cannabinoid toxicity during early development is due to inhibition of neuronal activity. To test these hypotheses we will perform in vivo and in vitro studies using contemporary neuroscience methods and CB1R knock-out mice. We anticipate that these studies will result in new insights into the potential effects of cannabinoid action on the developing brain.