Electrical role of dendritic spines

 描述(申请人提供)：树突棘是小突起，在大脑中调节大部分兴奋性突触传递。长期以来，它们的电结构和功能一直被认为是理解相互连接的神经元电路如何编码信息和调节行为的所有方面的关键。此外，许多关于神经和神经精神疾病的脊柱病理报告，包括唐氏综合症、自闭症、癫痫和精神分裂症，都强调了它们的临床相关性。尽管树突棘具有明确的生物学重要性，但对其电学结构和功能的完整和一致的描述尚不存在。为了应对这一挑战，一种新的高灵敏度光学记录方法被开发出来，用于监测来自单个树枝状刺的电事件的积分，树枝状刺是直径小于1微米的微小结构。这些以前从未可能实现的测量，为脊椎突触生理学研究的新方向铺平了道路。贴片电极是神经生理学的金标准，但在两个基本方面受到限制。首先，它只允许在附着点附近进行测量。其次，我们不能将吸管连接到小表面，如脊椎头部。一种新的电压成像方法解决了这两个问题。在概念层面上，一个尚未得到回答的基本问题是，通过狭窄的脊椎颈部对脊柱头部进行电隔离是否提供了树突上的突触所不具备的特定功能。基于模型和间接证据，已经推测了几种这样的功能，尽管它们还没有被直接或明确地证明：(1)脊髓标准化并增强了电压敏感通道的突触激活。(2)在活动控制下，颈椎电阻的变化参与了学习记忆形成的突触可塑性。(3)棘突的电学性质促进了非线性树突整合和相关形式的可塑性，从而从根本上提高了神经元的计算能力。(4)脊髓有能力作为一个离散的生电隔室，通过激活电压敏感通道来放大突触电位。对这些假设进行实验测试是至关重要的。如果得到证实，这些脊柱功能将确定它们的电作用，因此，将代表病理变化和治疗的潜在底物。一种新的光学记录将用于脑片，结合贴片电极记录、谷氨酸去化和计算模型，通过直接记录脊椎中的电信号来评估上述假设。这些测量将提供对树突棘的电结构的基本见解，这是至关重要的，或者理解神经元功能的生理学和病理学。

 DESCRIPTION (provided by applicant): Dendritic spines are small protrusions that mediate most of the excitatory synaptic transmission in the brain. Their electrical structure and function have long been recognized as essential for understanding how circuits of interconnected neurons encode information and mediate all aspects of behavior. Additionally, numerous reports of spine pathology in neurological and neuropsychiatric disorders including Down syndrome, autism, epilepsy, and schizophrenia highlight their clinical relevance. In spite of their clear biological importance, a complete and consistent description of the electrical structure and function of dendritic spines is not available. To meet this challenge, a novel method of high-sensitivity optical recording was developed to monitor integration of electrical events from individual dendritic spines, miniscule structures less than 1 micrometer in diameter. These measurements, which have never been possible before, pave the way to a new line of research in synaptic physiology of spines. The patch electrode is the gold standard in neurophysiology but is limited in two fundamental ways. First, it only allows measurement near the point of attachment. Second, we cannot attach pipettes to small surfaces, such as spine heads. A novel approach to voltage-imaging solves both these problems. At the conceptual level, a fundamental question that has not been answered is whether the electrical isolation of spine heads by a narrow spine neck provides specific functions which are not available to synapses on dendrites. Several such functions have been postulated, based on modeling and indirect evidence, although they have not been directly or definitively demonstrated: (1) Spines standardize and enhance synaptic activation of voltage-sensitive channels. (2) Changes in the electrical resistance of the spine neck under activity control mediate synaptic plasticity underlying learning and memory formation. (3) Electrical properties of spines promote nonlinear dendritic integration and associated forms of plasticity, thus fundamentally enhancing the computational capabilities of neurons. (4) Spines have the capacity to act as a discrete electrogenic compartments that amplify synaptic potentials by activation of voltage-sensitive channels. It is critical to test these postulates experimentally. If verified, these spine function would define their electrical role and, thus, would represent a potential substrate for pathologica changes and treatments. A novel optical recording will be used in brain slices combined with patch electrode recordings, glutamate uncaging, and computational models to evaluate the above hypotheses by direct recordings of electrical signaling in spines. These measurements will provide fundamental insight about the electrical structure of dendritic spines which is vital or understanding both physiology and pathology of neuronal function.