Activity-Dependent Synapse Refinement in the Memory Circuit in vivo

描述(由申请人提供)：功能神经回路的形成对大脑的正常运作至关重要。有人提出，在发育的特定时期，突触连接通过神经活动来精炼，以建立适当的神经回路。海马环路由高度组织化的单向突触连接组成：从内嗅皮层(EC)到齿状回(DG)，再到CA3、CA1和EC。然而，尽管众所周知，海马体对记忆形成、情绪处理和社会行为具有重要作用，但我们对海马体回路是否以及如何通过活动以及发生这种重塑的发育时期知之甚少。许多形式的精神疾病，如自闭症和精神分裂症，都与海马体回路的异常改变有关。因此，对改善海马区回路的方式的理解应该会对这些破坏性疾病的病因和治疗产生新的见解。在这里，我们建立了一个遗传系统来研究活体内活动在小鼠海马区神经回路建立和修改中的作用。在这个系统中，我们在体内有条件地灭活记忆回路中特定的神经元群体，并检查失活对神经连接的影响。我们首先研究了EC到DG和DG到CA3连接的改进。我们的初步结果表明，当胚胎阶段失活时，不活跃的EC和DG轴突仍然达到它们合适的靶点，但在短时间的发育过程中，通过与活跃轴突的活性依赖竞争而被消除。我们的数据还表明，EC和DG轴突在不同的发育阶段是精炼的。使用这个系统，我们将确定(1)活动何时对突触精化起重要作用，(2)敏感期的活动抑制是否导致永久性突触变化，(3)神经发生是否对DG内的突触精化起作用，(4)突触精化涉及哪些特定的突触变化，以及(5)微型和动作电位触发的神经传递是否在突触精化中发挥独特的作用。为此，我们建议：“目标1.确定依赖活动的突触细化的敏感和关键时期。”目的2.确定活动抑制在敏感期的功能后果。“目的3.研究神经发生在DG轴突细化中的作用。”目的4.研究突触细化过程中发生的突触事件。“目的5.研究微型和动作电位触发的神经传递在活动依赖型突触细化中的不同作用。通过这些研究，我们应该了解神经活动是如何在海马体中创建功能记忆回路的。预计我们的研究将帮助我们设计策略，预防和治疗与海马体回路异常形成相关的精神疾病，如自闭症和精神分裂症。”

DESCRIPTION (provided by applicant): Formation of functional neural circuits is critical for proper functioning of the brain. It has been proposed that synaptic connections are refined by neural activity during certain periods of development to establish appropriate neural circuits. Hippocampal circuits consist of highly organized unidirectional synaptic connections: from the entorhinal cortex (EC) to the dentate gyrus (DG) to CA3 to CA1 to the EC. However, despite the well known importance of the hippocampus to memory formation, emotional processing, and social behavior, we know very little about whether and how hippocampal circuits are refined by activity and the developmental periods over which such remodeling occurs. Many forms of mental illness such as autism and schizophrenia are associated with abnormal alterations in the hippocampal circuitry. Thus, the understanding of the manner by which hippocampal circuits are refined should yield novel insights into both the etiology and treatment of these devastating disorders. Here, we have established a genetic system to study the role of activity in the establishment and modification of neural circuits in the mouse hippocampus in vivo. In this system, we conditionally inactivate specific neuronal populations in the memory circuit for restricted periods of time in vivo and examine the effect of inactivation on neural connections. We first examined the refinement of EC-to-DG and DG-to-CA3 connections. Our preliminary results show that when inactivated from embryonic stages, inactive EC and DG axons still reach their appropriate target, but are eliminated during a short period of development by activity-dependent competition with active axons. Our data also suggest that EC and DG axons are refined at different developmental stages. Using this system, we will determine (1) when activity plays important roles for synapse refinement, (2) whether activity suppression during sensitive periods leads to permanent synaptic changes, (3) whether neurogenesis plays a role for synapse refinement in the DG, (4) what specific synaptic changes are involved in synapse refinement, and (5) whether miniature and action potential-triggered neurotransmission play unique roles in synapse refinement. For this, we propose to: " Aim 1. Identify the sensitive and critical periods for activity-dependent synapse refinement. " Aim 2. Determine the functional consequences of activity suppression during the sensitive periods. " Aim 3. Examine the role of neurogenesis in the refinement of DG axons. " Aim 4. Investigate what synaptic events take place during synapse refinement. " Aim 5. Examine the differential roles for miniature and action potential-triggered neurotransmission in activity- dependent synapse refinement. Through these studies we should understand how functional memory circuits are created in the hippocampus by neural activity. It is anticipated that our research will help us design strategies to prevent and treat mental illness associated with abnormal circuit formation in the hippocampus, such as autism and schizophrenia.