Targeting early-life intervention for treatment of neurodevelopmental disorders

在我们的生活中，我们将世界体验为我们所遇到的地点的一系列感觉和事件。典型发育的两个关键功能是我们的触觉和我们记住我们去过的地方的能力。这些能力以大脑回路为基础，当大脑正常运作时，我们就能对周围的世界产生一幅内部图像。这些大脑回路功能的改变会扰乱这些能力，并导致其他特征，如癫痫发作、焦虑、自闭症和感觉障碍。在患有神经发育疾病(如脆性X综合征)的人中可以观察到许多这样的特征，这些疾病共同严重损害了日常生活，需要大量的护理和医疗支持。脆性X综合征影响多达5000人中的1人，是最常见的、遗传的、导致智力残疾和自闭症的单基因原因，个人经常经历焦虑、癫痫和感觉障碍。这些特征中的许多都与个体脑细胞(神经元)的活动增加以及它们在生命早期发育过程中形成的回路直接相关。具体地说，这些特征通常出现在神经元最容易受到活动变化影响的生命期，这可能会导致电路功能的长期变化。这可能解释了为什么增加感觉体验可以使脆性X综合征患者受益，因为这直接支持这些大脑回路的成熟。然而，大多数治疗脆性X综合征的药物治疗试图在出现负面特征时解决它们(如癫痫和焦虑)。这种治疗方法意味着个人需要服用多种不同的药物来管理所经历的许多特征，这可能会导致广泛的副作用。因此，对于以尽可能多的功能为目标的新的脆性X综合征疗法，存在着一个严重的未得到满足的需求。其中一种方法是在许多临床特征出现之前，尝试并纠正早期生命中神经活动增加的问题。然而，大多数治疗脆性X综合征的新试验都是在发育后期进行的，甚至是在成年期进行的，错过了这一关键的发育阶段。其中一种名为BPN-14,770的药物针对的是过度的神经元活动，已被证明对患有脆性X综合征的成年人有利。然而，根据我们和其他人进行的研究，如果在大脑回路仍处于成熟状态时服用这种药物，实际上可能会对个人产生最深远和最持久的好处。为了解决这个问题，我们的研究旨在确定在生命早期发育过程中，BPN-14,770何时不仅可以纠正单个神经元功能的变化，还可以纠正它们形成的有助于以后生活行为的电路。在大多数情况下，这种水平的分析在脆性X个体中是不可能的，因为从大脑获取活的神经元既不符合伦理，也不可能。因此，在这项研究中，我们将使用脆性X综合征的大鼠模型来了解BPN-14,770如何纠正大脑回路中控制感觉处理和记忆形成的神经元的功能。我们将通过记录神经元的电活动来实现这一点，确定它们如何相互连接以及这些连接的强度；我们之前已经证明，在这个脆性X综合征大鼠模型中，这一点发生了改变。然后，我们将单独或与早期生命中增强的感官体验一起使用BPN-14,770。我们将测试的年龄与在儿童中发现脆性X综合征特征时的年龄大致匹配。我们将评估这些在生命早期给予这种治疗的人是否有可能在整个生命周期内纠正这种脆性X综合征大鼠模型的多种行为特征。这些研究的目的不仅是指导未来使用BPN-14,770的临床试验，而且还重新定义我们治疗其他神经发育疾病的方法。

During our lives we experience the world as a procession of sensations and events in locations that we encounter. Two critical functions for typical development are our sense of touch and our ability to remember places we have been. These abilities have a basis in brain circuits, which when functioning correctly allow us to generate an internal picture of the world around us. Changes to the function of these brain circuits can disrupt these abilities and lead to other features such as epileptic seizures, anxiety, autism, and sensory disturbances. Many such features are observed in individuals with neurodevelopmental conditions (such as Fragile X Syndrome), which together significantly impair day-to-day life, requiring substantial care and medical support. Fragile X Syndrome affects up to 1 in 5000 people, and is the most-common, inherited, single gene cause of intellectual disability and autism, with individuals often experiencing anxiety, epilepsy and sensory disturbances. Many of these features have been directly linked to the increased activity of individual brain cells (neurons) and the circuits they form during early-life development. Specifically, these features often appear during the life periods when neurons are most susceptible to changes in activity, which can lead to long-lasting changes in circuit function. This may explain why increased sensory experiences can benefits individuals with Fragile X Syndrome, as this directly supports the maturation of these brain circuits. However, most drug treatments for Fragile X Syndrome try to address negative features as they appear (such as epilepsy and anxiety). Such therapeutic approaches mean that multiple different drugs need to be taken by individuals to manage the many features experienced, which can lead to a wide range of side-effects. Therefore, there is a critical unmet need for new Fragile X Syndrome therapies that target as many features as possible. One such approach is to try and correct increased neural activity during early-life, before many clinical features emerge. However, most trials for new Fragile X Syndrome treatments are conducted later in development, or indeed in adulthood, missing this key developmental stage. One such drug, known as BPN-14,770, targets excessive neuronal activity, and has been shown to benefit adults with Fragile X Syndrome. However, based on research conducted by us and others, this drug may in fact produce the most profound and long-lasting benefits for individuals if given while brain circuits still maturing. To address this, our research aims to determine when during early-life development BPN-14,770 can correct changes not only single neuron function, but also the circuits they form that contribute to behaviour in later life. For the most part, this level of analysis is not possible in Fragile X individuals, as accessing living neurons from the brain is neither ethical nor possible. Therefore, for this research we will use a rat model of Fragile X Syndrome to understand how BPN-14,770 can correct the function of neurons in brain circuits that control sensory processing and memory formation. We will achieve this by recording the electrical activity of neurons, determining how they connect to each other and the strength of these connections; which we have previously shown to be altered in this Fragile X Syndrome rat model. We will then administer BPN-14,770, either alone or in combination with enhanced sensory experience during early life. The ages we will test broadly match those when features of Fragile X Syndrome are identified in children. We will assess if these giving this treatment earlier in life has the potential to correct multiple behavioural features of this Fragile X Syndrome rat model over the life-span. These research aims to direct not only future clinical trials using BPN-14,770, but also redefine our approach to the treatment of other neurodevelopmental conditions for generally.